{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:46:40Z","timestamp":1792201600177,"version":"4.4.0"},"reference-count":61,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007155","name":"Medical Research Council Canada","doi-asserted-by":"publisher","award":["MR\/M00032X\/1"],"award-info":[{"award-number":["MR\/M00032X\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\u03b12\u2010adrenoceptors, (\u03b12A, \u03b12B and \u03b12C\u2010subtypes), are Gi\u2010coupled receptors. Central activation of brain \u03b12A and \u03b12C\u2010adrenoceptors is the main site for \u03b12\u2010agonist mediated clinical responses in hypertension, ADHD, muscle spasm and ITU management of sedation, reduction in opiate requirements, nausea and delirium. However, despite having the same Gi\u2010potency in functional assays, some \u03b12\u2010agonists also stimulate Gs\u2010responses whilst others do not. This was investigated. Agonist responses to 49 different \u03b1\u2010agonists were studied (CRE\u2010gene transcription, cAMP, ERK1\/2\u2010phosphorylation and binding affinity) in CHO cells stably expressing the human \u03b12A, \u03b12B or \u03b12C\u2010adrenoceptor, enabling ligand intrinsic efficacy to be determined (binding K<jats:sub>D<\/jats:sub>\/Gi\u2010IC<jats:sub>50<\/jats:sub>). Ligands with high intrinsic efficacy (e.g., brimonidine and moxonidine at \u03b12A) stimulated biphasic (Gi\u2010Gs) concentration responses, however for ligands with low intrinsic efficacy (e.g., naphazoline), responses were monophasic (Gi\u2010only). ERK1\/2\u2010phosphorylation responses appeared to be Gi\u2010mediated. For Gs\u2010mediated responses to be observed, both a system with high receptor reserve and high agonist intrinsic efficacy were required. From the Gi\u2010mediated efficacy ratio, the degree of Gs\u2010coupling could be predicted. The clinical relevance and precise receptor conformational changes that occur, given the structural diversity of compounds with high intrinsic efficacy, remains to be determined. Comparison with \u03b11 and \u03b21\/\u03b22\u2010adrenoceptors demonstrated subclass affinity selectivity for some compounds (e.g., \u03b12:dexmedetomidine, \u03b11:A61603) whilst e.g., oxymetazoline had high affinity for both \u03b12A and \u03b11A\u2010subtypes, compared to all others. Some compounds had subclass selectivity due to selective intrinsic efficacy (e.g., \u03b12:brimonidine, \u03b11:methoxamine\/etilefrine). A detailed knowledge of these agonist characteristics is vital for improving computer\u2010based deep\u2010learning and drug design.<\/jats:p>","DOI":"10.1002\/prp2.1003","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T05:31:48Z","timestamp":1663133508000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["The signaling and selectivity of \u03b1\u2010adrenoceptor agonists for the human <scp>\u03b12A<\/scp>, <scp>\u03b12B<\/scp> and <scp>\u03b12C<\/scp>\u2010adrenoceptors and comparison with human \u03b11 and \u03b2\u2010adrenoceptors"],"prefix":"10.1002","volume":"10","author":[{"given":"Richard G. 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