50 years of hurdles and hope in anxiolytic drug discovery

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usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="STsZ8Txlm6ArXCKsj6ozuenEq1hZnyx8j5ei6x3xfJKCPqy0Qc31XmEb9anuwLXC"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="STsZ8Txlm6ArXCKsj6ozuenEq1hZnyx8j5ei6x3xfJKCPqy0Qc31XmEb9anuwLXC"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="STsZ8Txlm6ArXCKsj6ozuenEq1hZnyx8j5ei6x3xfJKCPqy0Qc31XmEb9anuwLXC"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="STsZ8Txlm6ArXCKsj6ozuenEq1hZnyx8j5ei6x3xfJKCPqy0Qc31XmEb9anuwLXC"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="23989795"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 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class="publication-type" >Review</div> <h1 class="heading-title"> 50 years of hurdles and hope in anxiolytic drug discovery </h1> <div class="short-citation"> <span class="authors-list"> <span class="authors-list-item "><span class="full-name">Guy Griebel</span><span class="citation-separator"> et al.</span></span> </span> <span class="citation-journal"> Nat Rev Drug Discov<span class="citation-separator">.</span> </span> <span class="date"> <span class="citation-year">2013 Sep</span><span class="citation-separator">.</span> </span> </div> <div class="more-article-details-section with-display-settings"> <button class="more-article-details" id="toggle-article-details" data-alt-text="Hide details" ref="linksrc=toggle_article_details" aria-controls="full-article-details" aria-expanded="false" data-fetch-url="/23989795/long-authors/" data-id-prefix=""> <span class="title">Show details</span> </button> <div class="display-options" data-format-key="format" 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"><a class="full-name" href="/?term=Holmes+A&cauthor_id=23989795" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Andrew Holmes">Andrew Holmes</a></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliation </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Sanofi, Exploratory Unit, Chilly-Mazarin 91385, France.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">23989795</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC4176700&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4176700/" data-ga-category="full_text" data-ga-action="PMCID" > 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<h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)-benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future. </p> </div> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one"><bold>Competing interests statement</bold></p> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare no competing financial interests.</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="figure-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/b15469720520/nihms628969f1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="701" data-image-height="443" data-image-alt="Figure 1" data-pmc-id="PMC4176700" data-figure-id="F1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/6eb86fbf50ad/nihms628969f1.gif" alt="Figure 1" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="701"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="443"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1. Fifty-year trends in preclinical anxiolytic… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1. Fifty-year trends in preclinical anxiolytic drug discovery </p> </strong> <div class="figure-caption-contents"><p> The values represent the number of… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1. Fifty-year trends in preclinical anxiolytic drug discovery </strong> <div class="figure-caption-contents">The values represent the number of experiments investigating the anxiety-related effects of targeting the 5-hydroxytryptamine (5-HT; also known as serotonin), neuropeptide, glutamate and endocannabinoid systems between 1960 and 2012. The graph shows that the volume of research steadily increased from the 1980s onwards, peaking at the end of the 1990s, and has remained relatively constant up to now. More than half of the experiments focused on the 5-HT system, but neuropeptide drugs have also been a major focus of anxiolytic drug discovery, accounting for about one-third of all experiments. Over the past decade, the field has seen a rise in studies focusing on the glutamate and endocannabinoid systems. In this figure, an experiment refers to one drug (single or multiple dosing) that is tested in one assay or model. For more information on each experiment, including the drug, preclinical model, results and references, see Supplementary information S1 (box).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="figure-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/31309fce604a/nihms628969f2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="800" data-image-height="603" data-image-alt="Figure 2" data-pmc-id="PMC4176700" data-figure-id="F2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/f5b82b09cdc9/nihms628969f2.gif" alt="Figure 2" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="603"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2. The ten most commonly used… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2. The ten most commonly used tests in anxiolytic drug discovery </p> </strong> <div class="figure-caption-contents"><p> The values represent… </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2. The ten most commonly used tests in anxiolytic drug discovery </strong> <div class="figure-caption-contents">The values represent the number of experiments performed with each test between 1960 and 2012. The elevated plus-maze test, the light/dark test and the open-field test have been a mainstay of anxiolytic drug discovery research for many years. They assay anxiety-like behaviour by generating a conflict between a drive to approach novel areas and, simultaneously, to avoid potential threat therein. They have clear intuitive appeal, are inexpensive to construct, and ostensibly quick and easy to run. The term ‘conflict-based test’ is also often used to describe measures of behaviour suppression by mild electric shock. This group includes the Vogel conflict and Geller-Seifter tests, which measure anxiolytic-like activity as the maintenance of a behavioural response (for example, licking or bar pressing) despite the receipt of a shock. Another set of fear-based tests involves variations on classical Pavlovian fear conditioning. Here, an animal learns to associate a context or specific environmental stimulus (for example, a light or a sound) with electric shock to produce a conditioned fear response that can be quantified in various ways (for example, freezing, escaping, avoidance or startle). Although the elevated plus-maze test, the light/dark test and the open-field test continue to be very popular, conflict-based tests — which were part of many drug discovery programmes in the 1980s and 1990s — are less frequently used today, perhaps because they require animals to be trained over multiple days and are more labour-intensive and time-consuming than the approach-avoidance tests.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="figure-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/708661f31c98/nihms628969f3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="800" data-image-height="461" data-image-alt="Figure 3" data-pmc-id="PMC4176700" data-figure-id="F3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/0ce6944ebd60/nihms628969f3.gif" alt="Figure 3" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="461"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3. Anxiety-related effects of drugs targeting… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3. Anxiety-related effects of drugs targeting the 5-HT, neuropeptide, glutamate and endocannabinoid systems </p> </strong> <div class="figure-caption-contents"><p> Findings… </p></div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3. Anxiety-related effects of drugs targeting the 5-HT, neuropeptide, glutamate and endocannabinoid systems </strong> <div class="figure-caption-contents">Findings from experiments conducted between 1960 and 2012 are shown as the percentage of experiments that showed anxiolytic-like, anxiogenic-like and inactive effects. The number of experiments reporting anxiolytic-like effects is shown on the graph. This figure shows that although compounds modulating the 5-hydroxytryptamine (5-HT), corticotropin-releasing factor (CRF), cholecystokinin (CCK), endocannabinoid and tachykinin systems have shown variable effects, compounds acting at several glutamatergic receptors (that is, metabotropic glutamate receptor 2 (mGluR2) and mGluR5), compounds targeting neuropeptide Y (NPY) and compounds that block melanin-concentrating hormone (MCH) receptors have all produced relatively consistent anxiolytic-like effects. CB<sub>1</sub>, cannabinoid 1; FAAH, fatty acid amide hydrolase; MPEP, 2-methyl-6-(phenylethynyl)pyridine; NK<sub>1</sub>, neurokinin 1; NMDA, <i>N</i>-methyl-D-aspartate; NPS, neuropeptide S; SSRI, selective serotonin reuptake inhibitor.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="figure-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/05d6cbc9a9cb/nihms628969f4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="800" data-image-height="564" data-image-alt="Figure 4" data-pmc-id="PMC4176700" data-figure-id="F4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/d6aefe3ddb7b/nihms628969f4.gif" alt="Figure 4" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="564"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4. Experiments in animal models that… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4. Experiments in animal models that investigated the effects of drugs modulating neuropeptide systems… </p> </strong> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4. Experiments in animal models that investigated the effects of drugs modulating neuropeptide systems in models of anxiety disorders from 1960 to 2012 </strong> <div class="figure-caption-contents">Seventeen different peptide systems have been suggested to have a role in the modulation of anxiety behaviours. This graph shows that, among them, corticotropin-releasing factor (CRF), the tachykinins and cholecystokinin (CCK) have been a major focus of anxiolytic drug discovery, accounting for about one-third of all experiments. MCH, melanin-concentrating hormone; NPS, neuropeptide S; NPY, neuropeptide Y; OFQ, orphanin FQ/nociceptin; TRH, thyrotropin-releasing hormone.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="figure-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/5051c5f3f5c8/nihms628969f5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="640" data-image-height="877" data-image-alt="Figure 5" data-pmc-id="PMC4176700" data-figure-id="F5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/f624bee4aa79/nihms628969f5.gif" alt="Figure 5" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="640"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="877"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5. Fifty-year trends in the species,… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5. Fifty-year trends in the species, strain, sex and chronicity of drug treatment in… </p> </strong> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5. Fifty-year trends in the species, strain, sex and chronicity of drug treatment in anxiolytic drug discovery studies </strong> <div class="figure-caption-contents">The values represent the absolute numbers and percentages of experiments performed with different species (part <b>a</b>), strains (parts <b>b, c, d</b>) and sexes (part <b>e</b>), regardless of whether these involved acute or chronic treatment (part <b>f</b>), between 1960 and 2012. Rats represented the species of choice for anxiety tests, but mice have been extensively used as well. In addition, the majority of studies have used male subjects (part <b>e</b>) rather than females, and tested the effects of drugs following acute treatment (part <b>f</b>) rather than chronic treatment.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="figure-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/99f90107b71d/nihms628969f6.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="634" data-image-height="746" data-image-alt="Figure 6" data-pmc-id="PMC4176700" data-figure-id="F6"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21d/4176700/cc2424d58eb3/nihms628969f6.gif" alt="Figure 6" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="634"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="746"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 6. Recommendations for improving anxiolytic drug… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 6. Recommendations for improving anxiolytic drug discovery </p> </strong> <div class="figure-caption-contents"><p> The figure details simple and actionable, rather… </p></div> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 6. Recommendations for improving anxiolytic drug discovery </strong> <div class="figure-caption-contents">The figure details simple and actionable, rather than idealized, suggestions and points to keep in mind. Although the early stages of the anxiolytic discovery process require high-throughput tests, these have generally limited predictive validity. Later-stage profiling using behavioural models with increased translatability potential could confirm or reject the initial findings, thereby increasing the probability of having selected the drug candidate with the highest anxiolytic potential. 5-HT, 5-hydroxytryptamine.</div> </figcaption> </figure> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="similar-articles" id="similar"> <h2 class="title"> Similar articles </h2> <ul class="articles-list" id="similar-articles-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/25727478/" ref="article_id=25727478&linksrc=similar_articles_link&ordinalpos=1" data-ga-category="similar_article" data-ga-action="25727478" data-ga-label=""> The failure of anxiolytic therapies in early clinical trials: what needs to be done. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Stewart AM, Nguyen M, Poudel MK, Warnick JE, Echevarria DJ, Beaton EA, Song C, Kalueff AV.</span> <span class="docsum-authors short-authors">Stewart AM, et al.</span> <span class="docsum-journal-citation full-journal-citation">Expert Opin Investig Drugs. 2015 Apr;24(4):543-56. doi: 10.1517/13543784.2015.1019063. 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href="/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Animals"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Animals"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Animals" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Animals"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Animals"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Animals"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Anti-Anxiety Agents / adverse effects" tabindex="0" aria-controls="keyword-actions-mesh-terms-1" aria-expanded="false" data-pinger-ignore> Anti-Anxiety Agents / adverse effects </button><div id="keyword-actions-mesh-terms-1" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Anti-Anxiety Agents / adverse effects"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Anti-Anxiety+Agents%2Fadverse+effects%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Anti-Anxiety+Agents%2Fadverse+effects%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Anti-Anxiety Agents/adverse effects"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Anti-Anxiety Agents / adverse effects"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Anti-Anxiety+Agents" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Anti-Anxiety Agents / adverse effects"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Anti-Anxiety Agents/adverse effects"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Anti-Anxiety Agents/adverse effects"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Anti-Anxiety Agents / pharmacology" tabindex="0" aria-controls="keyword-actions-mesh-terms-2" aria-expanded="false" data-pinger-ignore> Anti-Anxiety Agents / pharmacology </button><div id="keyword-actions-mesh-terms-2" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Anti-Anxiety Agents / pharmacology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Anti-Anxiety+Agents%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Anti-Anxiety+Agents%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Anti-Anxiety Agents/pharmacology"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Anti-Anxiety Agents / pharmacology"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Anti-Anxiety+Agents" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Anti-Anxiety Agents / pharmacology"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Anti-Anxiety Agents/pharmacology"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Anti-Anxiety Agents/pharmacology"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Anti-Anxiety Agents / therapeutic use*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-3" aria-expanded="false" data-pinger-ignore> Anti-Anxiety Agents / therapeutic use* </button><div id="keyword-actions-mesh-terms-major-3" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Anti-Anxiety Agents / therapeutic use*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Anti-Anxiety+Agents%2Ftherapeutic+use%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Anti-Anxiety+Agents%2Ftherapeutic+use%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Anti-Anxiety Agents/therapeutic use"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Anti-Anxiety Agents / therapeutic use*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Anti-Anxiety+Agents" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Anti-Anxiety Agents / therapeutic use*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Anti-Anxiety Agents/therapeutic use"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Anti-Anxiety Agents/therapeutic use"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Anxiety Disorders / drug therapy*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-4" aria-expanded="false" data-pinger-ignore> Anxiety Disorders / drug therapy* </button><div id="keyword-actions-mesh-terms-major-4" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Anxiety Disorders / drug therapy*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Anxiety+Disorders%2Fdrug+therapy%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Anxiety+Disorders%2Fdrug+therapy%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Anxiety Disorders/drug therapy"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Anxiety Disorders / drug therapy*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Anxiety+Disorders" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Anxiety Disorders / drug therapy*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Anxiety Disorders/drug therapy"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Anxiety Disorders/drug therapy"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Anxiety Disorders / epidemiology" tabindex="0" aria-controls="keyword-actions-mesh-terms-5" aria-expanded="false" data-pinger-ignore> Anxiety Disorders / epidemiology </button><div id="keyword-actions-mesh-terms-5" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Anxiety Disorders / epidemiology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Anxiety+Disorders%2Fepidemiology%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Anxiety+Disorders%2Fepidemiology%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Anxiety Disorders/epidemiology"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Anxiety Disorders / epidemiology"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Anxiety+Disorders" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Anxiety Disorders / epidemiology"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Anxiety Disorders/epidemiology"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Anxiety Disorders/epidemiology"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Anxiety Disorders / physiopathology" tabindex="0" aria-controls="keyword-actions-mesh-terms-6" aria-expanded="false" data-pinger-ignore> Anxiety Disorders / physiopathology </button><div id="keyword-actions-mesh-terms-6" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown 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role="button" data-search-term=""Anxiety Disorders/physiopathology"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Anxiety Disorders/physiopathology"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Clinical Trials as Topic" tabindex="0" aria-controls="keyword-actions-mesh-terms-7" aria-expanded="false" data-pinger-ignore> Clinical Trials as Topic </button><div id="keyword-actions-mesh-terms-7" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Clinical Trials as Topic"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Clinical+Trials+as+Topic%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Clinical+Trials+as+Topic%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Clinical Trials as Topic"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Clinical Trials as Topic"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Clinical+Trials+as+Topic" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Clinical Trials as Topic"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Clinical Trials as Topic"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Clinical Trials as Topic"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Disease Models, Animal" tabindex="0" aria-controls="keyword-actions-mesh-terms-8" aria-expanded="false" data-pinger-ignore> Disease Models, Animal </button><div id="keyword-actions-mesh-terms-8" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Disease Models, Animal"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Disease+Models%2C+Animal%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Disease+Models%2C+Animal%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Disease Models, Animal"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Disease Models, Animal"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" 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class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Drug+Design%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Drug+Design%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Drug Design"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Drug Design*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Drug+Design" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Drug Design*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Drug Design"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Drug Design"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Drug Discovery" tabindex="0" aria-controls="keyword-actions-mesh-terms-10" aria-expanded="false" data-pinger-ignore> Drug Discovery </button><div id="keyword-actions-mesh-terms-10" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Drug Discovery"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Drug+Discovery%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Drug+Discovery%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Drug Discovery"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Drug Discovery"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Drug+Discovery" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Drug Discovery"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Drug Discovery"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Drug Discovery"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Drug Evaluation, Preclinical" tabindex="0" aria-controls="keyword-actions-mesh-terms-11" aria-expanded="false" data-pinger-ignore> Drug Evaluation, Preclinical </button><div id="keyword-actions-mesh-terms-11" class="keyword-actions-dropdown dropdown dropdown-container" hidden 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role="button" data-search-term=""Drug Evaluation, Preclinical"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Drug Evaluation, Preclinical"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Humans" tabindex="0" aria-controls="keyword-actions-mesh-terms-12" aria-expanded="false" data-pinger-ignore> Humans </button><div id="keyword-actions-mesh-terms-12" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Humans"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc" 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Targeted Therapy </button><div id="keyword-actions-mesh-terms-13" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Molecular Targeted Therapy"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Molecular+Targeted+Therapy%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Molecular+Targeted+Therapy%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Molecular Targeted Therapy"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Molecular Targeted Therapy"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Molecular+Targeted+Therapy" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Molecular Targeted Therapy"> Search in 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50 years of hurdles and hope in anxiolytic drug discovery - PubMed