Binding and Functional Structure-activity Similarities of 4-substituted 2,5-dimethoxyphenyl Isopropylamine Analogues at 5-HT and 5-HT Serotonin Receptors

Overview

Journal Front Pharmacol

Date 2023 Feb 10

PMID 36762110

Authors

Prithvi Hemanth

Pallavi Nistala

Vy T Nguyen

Jose M Eltit

Richard A Glennon

Malgorzata Dukat

Affiliations

Soon will be listed here.

Abstract

Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT (h5-HT) serotonin receptor agonists. Activation of a related receptor population, h5-HT receptors, has been demonstrated to result in adverse effects including cardiac valvulopathy. We previously published on the binding of several such agents at the two receptor subtypes. We hypothesized that, due to their structural similarity, the 5-HT and 5-HT receptor affinities of these agents might be related, and that QSAR studies might aid future studies. For a series of 13 compounds, it is demonstrated here that i) their published rat brain 5-HT receptor affinities are significantly correlated with their h5-HT (r = 0.942) and h5-HT (r = 0.916) affinities, ii) as with r5-HT receptor affinity, h5-HT affinity is correlated with the lipophilicity of the 4-position substituent (r = 0.798), iii) that eight of the ten compounds examined in functional (Ca mobilization in stable cell lines generated expressing the human 5-HT receptor using the Flp-In T-REx system) assays acted as h5-HT agonists (4-substituent = H, F, Br, I, OCHCH, NO, CH, CH) and two (hexyl and benzyl) as antagonists, iv) h5-HT affinity but not action was correlated with the lipophilicity of the 4-position substituent (r = 0.750; = 10). The findings suggest that h5-HT receptor affinity, and its relationship to substituent lipophilicity, might be approximated by rat and h5-HT affinity but cannot be used as a predictor of h5-HT agonist action of 2,5-DMA analogs. Furthermore, given that certain 2,5-DMA analogs are on the clandestine market, their potential to produce cardiac side effects following persistent or chronic use activation of h5-HT receptors should be considered.

Citing Articles

Potent and Selective Human 5-HT Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity.

Tosh D, Pavan M, Clark A, Lammers J, Villano S, Marri S J Med Chem. 2024; 67(23):21264-21291.

PMID: 39589936 PMC: 11715225. DOI: 10.1021/acs.jmedchem.4c02174.

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review.

Glennon R, Dukat M ACS Pharmacol Transl Sci. 2024; 7(6):1722-1745.

PMID: 38898956 PMC: 11184610. DOI: 10.1021/acsptsci.4c00157.

Structure activity relationships of 5-HT and 5-HT serotonin receptor antagonists: N, C2 and 5'-Modified (N)-methanocarba-adenosine derivatives.

Tosh D, Calkins M, Ivancich M, Bock H, Campbell R, Lewicki S Eur J Med Chem. 2023; 259:115691.

PMID: 37562117 PMC: 10529765. DOI: 10.1016/j.ejmech.2023.115691.

References

Kolaczynska K, Luethi D, Trachsel D, Hoener M, Liechti M . Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines. Front Pharmacol. 2019; 10:1423. PMC: 6893898. DOI: 10.3389/fphar.2019.01423. View

Porter R, Benwell K, Lamb H, Malcolm C, Allen N, Revell D . Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol. 1999; 128(1):13-20. PMC: 1571597. DOI: 10.1038/sj.bjp.0702751. View

Luethi D, Widmer R, Trachsel D, Hoener M, Liechti M . Monoamine receptor interaction profiles of 4-aryl-substituted 2,5-dimethoxyphenethylamines (2C-BI derivatives). Eur J Pharmacol. 2019; 855:103-111. DOI: 10.1016/j.ejphar.2019.05.014. View

Rangisetty J, Dukat M, Dowd C, Herrick-Davis K, Dupre A, Gadepalli S . 1-[2-methoxy-5-(3-phenylpropyl)]-2-aminopropane unexpectedly shows 5-HT(2A) serotonin receptor affinity and antagonist character. J Med Chem. 2001; 44(20):3283-91. DOI: 10.1021/jm0100739. View

Glennon R . The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse. J Med Chem. 2017; 60(7):2605-2628. PMC: 5824997. DOI: 10.1021/acs.jmedchem.7b00085. View

Elangbam C . Drug-induced valvulopathy: an update. Toxicol Pathol. 2010; 38(6):837-48. DOI: 10.1177/0192623310378027. View

Ruchala I, Battisti U, Nguyen V, Chen R, Glennon R, Eltit J . Functional characterization of N-octyl 4-methylamphetamine variants and related bivalent compounds at the dopamine and serotonin transporters using Ca channels as sensors. Toxicol Appl Pharmacol. 2021; 419:115513. PMC: 8148225. DOI: 10.1016/j.taap.2021.115513. View

Setola V, Dukat M, Glennon R, Roth B . Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor. Mol Pharmacol. 2005; 68(1):20-33. DOI: 10.1124/mol.104.009266. View

Kursar J, Nelson D, Wainscott D, Cohen M, Baez M . Molecular cloning, functional expression, and pharmacological characterization of a novel serotonin receptor (5-hydroxytryptamine2F) from rat stomach fundus. Mol Pharmacol. 1992; 42(4):549-57. View

10.

Hopkins P, Polukoff G . Risk of valvular heart disease associated with use of fenfluramine. BMC Cardiovasc Disord. 2003; 3:5. PMC: 194859. DOI: 10.1186/1471-2261-3-5. View

11.

Dahl C, Allen M, Urie P, Hopkins P . Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals. BMC Med. 2008; 6:34. PMC: 2585088. DOI: 10.1186/1741-7015-6-34. View

12.

Huang X, Setola V, Yadav P, Allen J, Rogan S, Hanson B . Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment. Mol Pharmacol. 2009; 76(4):710-22. PMC: 2769050. DOI: 10.1124/mol.109.058057. View

13.

Shannon M, Battaglia G, Glennon R, Titeler M . 5-HT1 and 5-HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA). Eur J Pharmacol. 1984; 102(1):23-9. DOI: 10.1016/0014-2999(84)90333-9. View

14.

Nelson D, Lucaites V, Wainscott D, Glennon R . Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors. Naunyn Schmiedebergs Arch Pharmacol. 1999; 359(1):1-6. DOI: 10.1007/pl00005315. View

15.

Roth B . Drugs and valvular heart disease. N Engl J Med. 2007; 356(1):6-9. DOI: 10.1056/NEJMp068265. View

16.

Rothman R, Baumann M, SAVAGE J, Rauser L, McBride A, Hufeisen S . Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000; 102(23):2836-41. DOI: 10.1161/01.cir.102.23.2836. View

17.

Kolaczynska K, Luethi D, Trachsel D, Hoener M, Liechti M . Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines. Front Pharmacol. 2022; 12:794254. PMC: 8865417. DOI: 10.3389/fphar.2021.794254. View

18.

Seggel M, Yousif M, Lyon R, Titeler M, Roth B, Suba E . A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors. J Med Chem. 1990; 33(3):1032-6. DOI: 10.1021/jm00165a023. View

19.

Steele T, Spires Z, Jones C, Glennon R, Dukat M, Eltit J . Non-conserved residues dictate dopamine transporter selectivity for the potent synthetic cathinone and psychostimulant MDPV. Neuropharmacology. 2021; 200:108820. PMC: 8549013. DOI: 10.1016/j.neuropharm.2021.108820. View

20.

Glennon R, Liebowitz S, Mack E . Serotonin receptor binding affinities of several hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogues. J Med Chem. 1978; 21(8):822-5. DOI: 10.1021/jm00206a022. View