5-HT2 receptor binding, functional activity and selectivity in N-benzyltryptamines

Miguel A Toro-Sazo; José Brea; María I. Loza; Marta Cimadevila; Bruce K. Cassels

doi:10.1371/journal.pone.0209804

5-HT2 receptor binding, functional activity and selectivity in N-benzyltryptamines

Miguel A Toro-Sazo, José Brea, María I. Loza, Marta Cimadevila, Bruce K. Cassels

PLoS One January 10, 2019 DOI: 10.1371/journal.pone.0209804 (opens in new tab)

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AI-extracted from the abstract

Characteristics	In vitro pharmacological study Peer reviewed
Topics	Serotonin
Key points	All synthesized N-benzyltryptamines acted as full agonists at 5-HT2C receptors, while most showed low efficacy at 5-HT2A despite some binding 5-HT2A with affinities in the 10-100 nanomolar range. Several compounds preferentially activated 5-HT2C at nanomolar concentrations, suggesting some may be abuse-liable and others potential therapeutic leads.

Abstract

The last fifteen years have seen the emergence and overflow into the drug scene of "superpotent" N-benzylated phenethylamines belonging to the "NBOMe" series, accompanied by numerous research articles. Although N-benzyl substitution of 5-methoxytryptamine is known to increase its affinity and potency at 5-HT2 receptors associated with psychedelic activity, N-benzylated tryptamines have been studied much less than their phenethylamine analogs. To further our knowledge of the activity of N-benzyltryptamines, we have synthesized a family of tryptamine derivatives and, for comparison, a few 5-methoxytryptamine analogs with many different substitution patterns on the benzyl moiety, and subjected them to in vitro affinity and functional activity assays vs. the human 5-HT2 receptor subtypes. In the binding (radioligand displacement) studies some of these compounds exhibited only modest selectivity for either 5-HT2A or 5-HT2C receptors suggesting that a few of them, with affinities in the 10-100 nanomolar range for 5-HT2A receptors, might presumably be psychedelic. Unexpectedly, their functional (calcium mobilization) assays reflected very different trends. All of these compounds proved to be 5-HT2C receptor full agonists while most of them showed low efficacy at the 5-HT2A subtype. Furthermore, several showed moderate-to-strong preferences for activation of the 5-HT2C subtype at nanomolar concentrations. Thus, although some N-benzyltryptamines might be abuse-liable, others might represent new leads for the development of therapeutics for weight loss, erectile dysfunction, drug abuse, or schizophrenia.

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