Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT) 2A Receptor (5-HT 2A R), 5-HT 2C R, 5-HT 1A R, and Serotonin Transporter.

Autor:	Kozell LB; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Eshleman AJ; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Swanson TL; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Bloom SH; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Wolfrum KM; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Schmachtenberg JL; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Olson RJ; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Janowsky A; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon., Abbas AI; Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon abbasat@ohsu.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 Apr; Vol. 385 (1), pp. 62-75. Date of Electronic Publication: 2023 Jan 20.
DOI:	10.1124/jpet.122.001454
Abstrakt:	Novel psychoactive substances, including synthetic substituted tryptamines, represent a potential public health threat. Additionally, some substituted tryptamines are being studied under medical guidance as potential treatments of psychiatric disorders. Characterizing the basic pharmacology of substituted tryptamines will aid in understanding differences in potential for harm or therapeutic use. Using human embryonic kidney cells stably expressing 5-hydroxytryptamine (5-HT) 1A , 5-HT 2A , and 5-HT 2C receptors (5-HT 1A R, 5-HT 2A R, and 5HT 2C R, respectively) or the serotonin transporter (SERT), we measured affinities, potencies and efficacies of 21 substituted tryptamines. With the exception of two 4-acetoxy compounds, substituted tryptamines exhibited affinities and potencies less than one micromolar at the 5-HT 2A R, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HT 2C R, 5-HT 1A R, and SERT. Sorting by the ratio of 5-HT 2A to 5-HT 2C , 5-HT 1A , or SERT affinity revealed chemical determinants of selectivity. We found that although 4-substituted compounds exhibited affinities that ranged across a factor of 100, they largely exhibited high selectivity for 5-HT 2A Rs versus 5-HT 1A Rs and 5-HT 2C Rs. 5-substituted compounds exhibited high affinities for 5-HT 1A Rs, low affinities for 5-HT 2C Rs, and a range of affinities for 5-HT 2A Rs, resulting in selectivity for 5-HT 2A Rs versus 5-HT 2C Rs but not versus 5-HT 1A Rs. Additionally, a number of psychedelics bound to SERT, with non-ring-substituted tryptamines most consistently exhibiting binding. Interestingly, substituted tryptamines and known psychedelic standards exhibited a broad range of efficacies, which were lower as a class at 5-HT 2A Rs compared with 5-HT 2C Rs and 5-HT 1A Rs. Conversely, coupling efficiency/amplification ratio was highest at 5-HT 2A Rs in comparison with 5-HT 2C Rs and 5-HT 1A Rs. SIGNIFICANCE STATEMENT: Synthetic substituted tryptamines represent both potential public health threats and potential treatments of psychiatric disorders. The substituted tryptamines tested differed in affinities, potencies, and efficacies at 5-hydroxytryptamine (5-HT) 2A , 5-HT 2C , and 5HT 1A receptors and the serotonin transporter (SERT). Several compounds were highly selective for and coupled very efficiently downstream of 5-HT 2A versus 5-HT 1A and 5-HT 2C receptors, and some bound SERT. This basic pharmacology of substituted tryptamines helps us understand the pharmacologic basis of their potential for harm and as therapeutic agents. (U.S. Government work not protected by U.S. copyright.)
Databáze:	MEDLINE
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