{"doi":"10.1111/bph.13034","title":"<scp>AT</scp>‐1001: a high‐affinity α3β4 <scp>nAChR</scp> ligand with novel nicotine‐suppressive pharmacology","abstract":"<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>The α3β4 subtype of nicotinic acetylcholine receptors (<jats:styled-content style=\"fixed-case\">nAChRs</jats:styled-content>) has been implicated in mediating nicotine reinforcement processes. <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 has been recently described as a high‐affinity and selective α3β4 <jats:styled-content style=\"fixed-case\">nAChR</jats:styled-content> antagonist that blocks nicotine self‐administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine‐suppressive effects of <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>Effects of <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 were determined using <jats:italic>in vitro</jats:italic> assays and rat models of nicotine addiction, and compared with varenicline.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p><jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 and its analogue <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1012 were functionally selective as antagonists for α3β4 over α4β2 <jats:styled-content style=\"fixed-case\">nAChRs</jats:styled-content>, but not to the same extent as the binding selectivity, and had partial agonist activity at α3β4 <jats:styled-content style=\"fixed-case\">nAChRs</jats:styled-content>. In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 <jats:styled-content style=\"fixed-case\">nAChRs</jats:styled-content>. <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 and varenicline also had very different <jats:italic>in vivo</jats:italic> properties. Firstly, <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 did not exhibit reinforcing properties <jats:italic>per se</jats:italic> while varenicline was self‐administered. Secondly, systemic treatment with <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 selectively blocked nicotine self‐administration without altering alcohol lever pressing as assessed in an operant co‐administration paradigm.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>These findings describe a more complex <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 <jats:italic>in vitro</jats:italic> profile than previously appreciated and provide further support for the potential of <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications.</jats:p></jats:sec>","journal":"British Journal of Pharmacology","year":2015,"id":647982,"datarank":1.1646408319554586,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.6313386227320467,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.6313386227320467,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":23,"citers_with_citation_signal":22,"citers_with_endowment":22,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":149541,"name":"Jinhua Wu","orcid":null,"position":1,"is_corresponding":false},{"id":1688438,"name":"Kelly A Gaiolini","orcid":null,"position":2,"is_corresponding":false},{"id":1688441,"name":"Daniela Mercatelli","orcid":null,"position":3,"is_corresponding":false},{"id":1688446,"name":"Jennifer Schoch","orcid":null,"position":4,"is_corresponding":false},{"id":1688447,"name":"Michelle Gorman","orcid":null,"position":5,"is_corresponding":false},{"id":1688450,"name":"Alejandra Ramirez","orcid":null,"position":6,"is_corresponding":false},{"id":445278,"name":"Roberto Ciccocioppo","orcid":"0000-0003-3126-9240","position":7,"is_corresponding":false},{"id":1688456,"name":"Taline V Khroyan","orcid":null,"position":8,"is_corresponding":false},{"id":1585555,"name":"Dennis Yasuda","orcid":null,"position":9,"is_corresponding":false},{"id":1688460,"name":"Nurulain T Zaveri","orcid":null,"position":10,"is_corresponding":false},{"id":1688462,"name":"Conrado Pascual","orcid":null,"position":11,"is_corresponding":false},{"id":1688463,"name":"Xinmin (Simon) Xie","orcid":null,"position":12,"is_corresponding":false},{"id":443580,"name":"Lawrence Toll","orcid":"0000-0002-4501-7573","position":13,"is_corresponding":false},{"id":480431,"name":"Andrea Cippitelli","orcid":"0000-0001-8151-0579","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"<scp>AT</scp>‐1001: a high‐affinity α3β4 <scp>nAChR</scp> ligand with novel nicotine‐suppressive pharmacology","abstract":"<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>The α3β4 subtype of nicotinic acetylcholine receptors (<jats:styled-content style=\"fixed-case\">nAChRs</jats:styled-content>) has been implicated in mediating nicotine reinforcement processes. <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 has been recently described as a high‐affinity and selective α3β4 <jats:styled-content style=\"fixed-case\">nAChR</jats:styled-content> antagonist that blocks nicotine self‐administration in rats. 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In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 <jats:styled-content style=\"fixed-case\">nAChRs</jats:styled-content>. <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 and varenicline also had very different <jats:italic>in vivo</jats:italic> properties. Firstly, <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 did not exhibit reinforcing properties <jats:italic>per se</jats:italic> while varenicline was self‐administered. Secondly, systemic treatment with <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 selectively blocked nicotine self‐administration without altering alcohol lever pressing as assessed in an operant co‐administration paradigm.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>These findings describe a more complex <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 <jats:italic>in vitro</jats:italic> profile than previously appreciated and provide further support for the potential of <jats:styled-content style=\"fixed-case\">AT</jats:styled-content>‐1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25440006","pmcid":"PMC4376460","openalex_id":"https://openalex.org/W2097505823","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"1R01DA020811","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R01 DA023281","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R44 NS086343","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R01 DA020811","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R44 DA033744","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01DA020811-05","title":"Subtype-Selective Nicotinic Receptor Ligands as Smoking Cessation Pharmacotherapy"},{"funder_name":"State of Florida Executive Office of the Governor’s Department of Economic Opportunity","grant_id":"","title":null}],"total_grants":7,"fwci":1.3015,"citation_percentile":0.79485754,"influential_citations":0,"citation_trend":[{"year":2015,"count":4},{"year":2016,"count":3},{"year":2017,"count":3},{"year":2018,"count":4},{"year":2019,"count":6},{"year":2020,"count":4},{"year":2021,"count":1},{"year":2022,"count":4},{"year":2023,"count":4},{"year":2026,"count":1}],"oa_status":"bronze","license":"Wiley Online Library User Agreement","oa_locations":[{"url":"https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bph.13034","host_type":"journal"},{"url":"https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bph.13034","host_type":"publisher"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fbph.13034","host_type":"publisher"},{"url":"https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13034","host_type":"publisher"},{"url":"https://doi.org/10.1111/bph.13034","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25440006","host_type":"repository"},{"url":"http://hdl.handle.net/11392/2335911","host_type":"repository"},{"url":"http://hdl.handle.net/11581/387826","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4376460","host_type":"repository"},{"url":"https://dx.doi.org/10.1111/bph.13034","host_type":""},{"url":"https://hdl.handle.net/11581/387826","host_type":""},{"url":"https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.13034","host_type":""},{"url":"https://hdl.handle.net/11392/2335911","host_type":""},{"url":"http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1476-5381","host_type":""}],"fields_of_study":["Nicotinic Acetylcholine Receptors Study","Vagus Nerve Stimulation Research","Ion channel regulation and function","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Varenicline","Ethanol","Animals","Cell Line","Humans","Ligands","Male","Motor Activity","Nicotine","Oligopeptides","Receptors, Nicotinic","Rats, Sprague-Dawley","Nicotinic Agonists","Nicotinic Antagonists","Drug-Seeking Behavior"],"keywords":["Varenicline","Nicotine","Partial agonist","Pharmacology","Agonist","Nicotinic agonist","Chemistry","Antagonist","Acetylcholine receptor","Self-administration","Nicotinic acetylcholine receptor","Receptor","Medicine","Internal medicine","Biochemistry","Male","Ethanol","Drug-Seeking Behavior","Nicotinic Antagonists","Motor Activity","Receptors, Nicotinic","Ligands","Cell Line","Rats, Sprague-Dawley","Animals; Cell Line; Drug-Seeking Behavior; Ethanol; Humans; Ligands; Male; Motor Activity; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Oligopeptides; Rats, Sprague-Dawley; Receptors, Nicotinic; Varenicline; Pharmacology","Animals","Humans","Nicotinic Agonists","Oligopeptides"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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