1-Aminomethylbenzocycloalkanes:  Conformationally Restricted Hallucinogenic Phenethylamine Analogues as Functionally Selective 5-HT_2A Receptor Agonists

Abstract

A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy-4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT(2A) receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream signaling pathways, and one exceptional compound was selected for testing in an in vivo drug discrimination model of hallucinogenesis. All compounds were examined in silico by virtual docking into a homology model of the 5-HT(2A) receptor. On the basis of these docking experiments, it was predicted that the R enantiomer of benzocyclobutene analogue 2 would be the most potent. Subsequent chemical resolution and X-ray crystallography confirmed this prediction, as (R)-2 proved to be equipotent to LSD in rats trained to discriminate LSD from saline. Thus, we propose that the conformation of 2 mimics the active binding conformation of the more flexible phenethylamine type hallucinogens. In addition, (R)-2 is one of the most potent and selective compounds yet discovered in the in vivo drug discrimination assay. Further, 2 was found to be a functionally selective agonist at the 5-HT(2A) receptor, having 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT(2A) receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

“…An increased expression of KCC2 in the plasma membrane, at least in part, provides the molecular basis of this restoration. (Table S1), to further identify the subtype of 5-HT 2 R that are involved, we used (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2), a high-affinity 5-HT 2A R agonist (21,22) (Table S1). TCB-2 at low concentration (0.1 μM; n = 6) hyperpolarized E IPSP by ∼4 mV in control rats ( Fig.…”

Structure–activity relationships of serotonin 5‐HT2A agonists

“…80,106 In addition, virtual docking studies allowed the design of new agonist ligands as well as the prediction of their more active enantiomers. 104,105 More recently, Isberg et al 79 have developed an in silico-activated model of the 5-HT 2A receptor starting with the published crystal structure of the β-2-adrenergic receptor. Continued refinements of this, and other G protein coupled receptors, will ultimately allow a greater understanding of the molecular features that lead to receptor binding and activation.…”

“…Contracting the five-membered ring to a cyclobutene, however, gave highly potent 64, (3-bromo-2,5-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine, known as TCB-2. 105 Virtual docking of this molecule to a homology model of the receptor also had predicted that the R enantiomer would be most active. Indeed, pharmacological evaluation revealed that the R benzocyclobutene 64 had a K i of 0.26 nM, while the S isomer had a K i of only 42 nM.…”

Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

“…The heptahelical serotonin 2A receptor (5-HT2AR) is a GPCR that couples primarily with Gq proteins, yet several cellular studies have shown that this receptor can have different signaling and trafficking profiles depending on the nature of the ligand bound (1,(10)(11)(12)(13)(14)(15). However, such divergences in ligand-directed signaling have yet to be correlated with drug-induced behaviors.…”