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

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.

Psychedelic-like Activity of Norpsilocin Analogues

“…This is especially evident in the emergence of the N -benzylmethoxy (NBOMe) phenethylamine series, particularly the 25x-NBOMe derivatives, which have considerably higher potency and unexpected properties compared to their non- N -benzyl-substituted counterparts. − For instance, 25I-NBOMe, one of the most studied in the series, has high potency at the 5-HT 2A receptor, along with serious toxicological side effects atypical of classical psychedelics . Subsequent studies might evaluate the impact of analogous substitutions on the phenyl ring of 4-HO-NBnT to ascertain additional structure–activity relationships, adding to recent reports evaluating related substituted N -benzyltryptamines. , …”

“…47 Subsequent studies might evaluate the impact of analogous substitutions on the phenyl ring of 4-HO-NBnT to ascertain additional structure−activity relationships, adding to recent reports evaluating related substituted N-benzyltryptamines. 48,49 Functional Activity at 5-HT 1,4,5,6,7 Receptors. In addition to the 5-HT 2 receptor calcium mobilization assays, the functional agonist activity of the norpsilocin analogues was also screened across an array of other non 5-HT 2 receptor subtypes using the GPCR Tango assay measuring G proteinindependent β-arrestin recruitment (Figure 6, Figure S7).…”

Dibenzofuranylethylamines as 5-HT2A/2C Receptor Agonists

“… a Values represent the mean ± range of two independent assays with duplicate measurements. b %maximum response (5-HT) at 100 μM. c Data from Luethi et al, 2018 d ND, not determined. e Data from Toro et al, 2019 f NA, not active.…”

Serotonin: an overlooked regulator of endocytosis and endosomal sorting?

“…In vivo , plasma (excluding platelets) serotonin levels are ∼1-3 nM ( Brand and Anderson, 2011 ). The half-maximal effective concentration (EC 50 ) of 5-HT 2A is 8.09 nM and that of 5-HT 2C is 9.87 nM ( Toro-Sazo et al, 2019 ), while the Michaelis constant (Km) of the serotonin affinity of SERT is 463 nM ( Ramamoorthy et al, 1993 ). Serotonin signalling is therefore likely to predominate, albeit to a very limited degree, in conditions with basal serotonin levels, with little serotonin available for entering the cell or binding the plasma membrane.…”