{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:53:01Z","timestamp":1790693581185,"version":"4.1.0"},"reference-count":51,"publisher":"American Chemical Society (ACS)","issue":"3","license":[{"start":{"date-parts":[[2016,1,14]],"date-time":"2016-01-14T00:00:00Z","timestamp":1452729600000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["U01MH105892"],"award-info":[{"award-number":["U01MH105892"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,3,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand\u2013receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure\u2013activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with &amp;gt;10\u202f000-fold selectivity for hM3Dq over hM3.<\/jats:p>","DOI":"10.1021\/cn500325v","type":"journal-article","created":{"date-parts":[[2015,1,14]],"date-time":"2015-01-14T12:11:13Z","timestamp":1421237473000},"page":"476-484","source":"Crossref","is-referenced-by-count":156,"title":["The First Structure\u2013Activity Relationship Studies\nfor Designer Receptors Exclusively Activated by Designer Drugs"],"prefix":"10.1021","volume":"6","author":[{"given":"Xin","family":"Chen","sequence":"first","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai , , , ,","place":["New York, New York, United States, 10029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunah","family":"Choo","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill National Institute of Mental Health - Psychoactive Drug Screening Program, , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]},{"name":"Korea Institute of Science and Technology , , ,","place":["Seongbuk-gu, Seoul, Republic of Korea, 136-791"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi-Ping","family":"Huang","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill National Institute of Mental Health - Psychoactive Drug Screening Program, , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobao","family":"Yang","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai , , , ,","place":["New York, New York, United States, 10029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orrin","family":"Stone","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill National Institute of Mental Health - Psychoactive Drug Screening Program, , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan L.","family":"Roth","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill National Institute of Mental Health - Psychoactive Drug Screening Program, , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Jin","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai , , , ,","place":["New York, New York, United States, 10029"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2015,1,14]]},"reference":[{"key":"2026090302291589200_cit1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev-neuro-071013-014048","article-title":"Chemogenetic Tools to Interrogate Brain Functions","volume":"37","author":"Sternson","year":"2014","journal-title":"Annu. 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Neurosci."},{"key":"2026090302291589200_cit9","doi-asserted-by":"crossref","first-page":"17816","DOI":"10.1073\/pnas.0509030102","article-title":"Fast noninvasive activation\nand inhibition of neural\nand network activity by vertebrate rhodopsin and green algae channelrhodopsin","volume":"102","author":"Li","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026090302291589200_cit10","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/nn.2120","article-title":"Red-shifted\noptogenetic excitation: a tool for fast neural control derived from Volvox carteri","volume":"11","author":"Zhang","year":"2008","journal-title":"Nat. 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A."},{"key":"2026090302291589200_cit21","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1126\/science.1205295","article-title":"Impaired Respiratory and Body Temperature\nControl Upon Acute Serotonergic Neuron Inhibition","volume":"333","author":"Ray","year":"2011","journal-title":"Science"},{"key":"2026090302291589200_cit22","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1126\/science.1214985","article-title":"Generation of a synthetic\nmemory trace","volume":"335","author":"Garner","year":"2012","journal-title":"Science"},{"key":"2026090302291589200_cit23","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/nature11270","article-title":"Deconstruction\nof\na neural circuit for hunger","volume":"488","author":"Atasoy","year":"2012","journal-title":"Nature"},{"key":"2026090302291589200_cit24","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature12956","article-title":"An excitatory paraventricular\nnucleus to AgRP neuron circuit that drives hunger","volume":"507","author":"Krashes","year":"2014","journal-title":"Nature"},{"key":"2026090302291589200_cit25","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nature12485","article-title":"A disinhibitory microcircuit initiates critical-period\nplasticity in the visual cortex","volume":"501","author":"Kuhlman","year":"2013","journal-title":"Nature"},{"key":"2026090302291589200_cit26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nature12596","article-title":"Genetic identification\nof a neural circuit that suppresses appetite","volume":"503","author":"Carter","year":"2013","journal-title":"Nature"},{"key":"2026090302291589200_cit27","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nature11810","article-title":"Genetic\nidentification of C fibres that detect massage-like stroking of hairy\nskin in vivo","volume":"493","author":"Vrontou","year":"2013","journal-title":"Nature"},{"key":"2026090302291589200_cit28","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nature11052","article-title":"Recurrent\nnetwork activity drives striatal synaptogenesis","volume":"485","author":"Kozorovitskiy","year":"2012","journal-title":"Nature"},{"key":"2026090302291589200_cit29","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nn.2703","article-title":"Transient neuronal\ninhibition reveals opposing roles of indirect and direct pathways\nin sensitization","volume":"14","author":"Ferguson","year":"2011","journal-title":"Nat. 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