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

  • ️Thu Jan 01 2015

Comparative Study

. 2015 Jul 15;6(7):1165-75.

doi: 10.1021/cn500292d. Epub 2015 Jan 21.

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Comparative Study

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

David E Nichols et al. ACS Chem Neurosci. 2015.

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 Ca(2+) 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 twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor.

Keywords: 5-HT2 receptors; 5-HT2A; 5-methoxytryptamine; Serotonin; agonist; mouse head twitch; phenethylamine.

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Figures

Figure 1
Figure 1

Representative dose–response plot in the mouse head twitch assay for compound 5h. *p < 0.05 versus vehicle (Tukey’s test).

Figure 2
Figure 2

Plots of active and inactive compounds as a function of potency and efficacy at the rat 5-HT2A receptor (panel A) and the human 5-HT2A receptor (panel B).

Figure 3
Figure 3

Regression analysis of pED50 for the mouse head twitch response on the pEC50 for function for active compounds at the rat 5-HT2A receptor; n = 10.

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