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Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT 2 Receptor Agonist.

التفاصيل البيبلوغرافية
العنوان: Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT 2 Receptor Agonist.
المؤلفون: Varty GB; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland., Canal CE; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland.; College of Pharmacy, Department of Pharmaceutical Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, Georgia 30341, United States., Mueller TA; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland.; BioIVT, Hicksville, New York 11803, United States., Hartsel JA; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland.; Consultant, UPS PO Box #105-650, 25422 Trabuco Road, Lake Forest, California 92630, United States., Tyagi R; College of Pharmacy, Department of Pharmaceutical Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, Georgia 30341, United States., Avery K; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland., Morgan ME; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland., Reichelt AC; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland.; Faculty of Biomedicine, University of Adelaide, Adelaide, South Australia 5005, Australia., Pathare P; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland., Stang E; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland., Palfreyman MG; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland., Nivorozhkin A; Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland.
المصدر: Journal of medicinal chemistry [J Med Chem] 2024 Apr 25; Vol. 67 (8), pp. 6144-6188. Date of Electronic Publication: 2024 Apr 09.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Phenethylamines*/pharmacology , Phenethylamines*/chemistry , Phenethylamines*/chemical synthesis , Serotonin 5-HT2 Receptor Agonists*/pharmacology , Serotonin 5-HT2 Receptor Agonists*/chemistry , Serotonin 5-HT2 Receptor Agonists*/chemical synthesis, Structure-Activity Relationship ; Animals ; Humans ; Administration, Oral ; Male ; Biological Availability ; Rats ; Mice ; Rats, Sprague-Dawley ; Drug Discovery ; Receptors, Serotonin, 5-HT2/metabolism ; Receptor, Serotonin, 5-HT2A/metabolism
مستخلص: Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT 2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT 2A and 5-HT 2C receptors, modest selectivity over 5-HT 2B , 5-HT 1A , 5-HT 6 , and adrenergic α 2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT 2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT 2 receptor activation. In addition, several other compounds with high 5-HT 2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT 2A receptor ligands.
المشرفين على المادة: 0 (Phenethylamines)
0 (Serotonin 5-HT2 Receptor Agonists)
0 (Receptors, Serotonin, 5-HT2)
0 (Receptor, Serotonin, 5-HT2A)
تواريخ الأحداث: Date Created: 20240409 Date Completed: 20240425 Latest Revision: 20240425
رمز التحديث: 20240425
DOI: 10.1021/acs.jmedchem.3c01961
PMID: 38593423
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.3c01961