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N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylarnine Analogues

Nichols, DE and Sassano, MF and Halberstadt, AL and Klein, LM and Brandt, SD and Elliott, SP and Fiedler, WJ (2015) N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylarnine Analogues. ACS CHEMICAL NEUROSCIENCE, 6 (7). pp. 1165-1175. ISSN 1948-7193

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Abstract

A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5- dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca2+ mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head.

Item Type: Article
Uncontrolled Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences; Pharmacology & Pharmacy; Neurosciences & Neurology; Serotonin; 5-HT2 receptors; 5-HT2A; agonist; phenethylamine; S-methoxytryptamine; mouse head twitch; HALLUCINOGEN-LIKE ACTIONS; HEAD-TWITCH BEHAVIOR; MICE; MODEL; TRYPTAMINES; ERGOLINES; 25I-NBOME; RATS
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: AMER CHEMICAL SOC
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Date Deposited: 16 Mar 2016 12:59
Last Modified: 16 Mar 2016 12:59
DOI or Identification number: 10.1021/cn500292d
URI: http://researchonline.ljmu.ac.uk/id/eprint/3198

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