Extensive Rigid Analogue Design Maps the Binding Conformation of Potent N-Benzylphenethylamine 5-HT_2A Serotonin Receptor Agonist Ligands

Abstract

Based on the structure of the superpotent 5-HT 2A agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ringsubstituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogues to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted of diversely substituted tetrahydroisoquinolines, piperidines, and one benzazepine. Based on the structure of (S,S)-9b, which showed the highest affinity of the series, we propose an optimal binding conformation. (S,S)-9b also displayed 124-fold selectivity for the 5-HT 2A over the 5-HT 2C receptor, making it the most selective 5-HT 2A receptor agonist ligand currently known.

Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents

“…There have been no consistent differences in the potency and efficacy of these compounds at the various monoaminergic receptors or transporters (Cozzi & Daley, 2016; Gatch et al, 2011; Goodwin et al, in submission; Nagai et al, 2007) that might account for the differing patterns of substitution for various training drugs or for their effects on locomotor activity. Similarly, there are no differences in potency or selectivity for 5-HT 2A/C receptors among the compounds tested in the present study (Juncosa et al, 2013; Rickli et al, 2015). Furthermore, the potencies for off-target receptors (D1, alpha-2, etc.)…”

“…Furthermore, the potencies for off-target receptors (D1, alpha-2, etc.) are roughly 1000-fold lower for each compound than for 5HT 2A/C , so non-serotonergic effects seem unlikely (Juncosa et al, 2013; Rickli et al, 2015). …”

“…The NBOMe compounds have high affinity for the 5-HT 2A and 5-HT 2C receptors (Juncosa et al, 2013; Rickli et al, 2015), with much lower potencies observed for other receptors (e.g., 3000–7100 fold more selective for 5-HT 2A over 5-HT 1A ). Lower-affinity binding was observed for α1 adrenergic and H1 histaminergic receptors, and very low levels of binding were seen to monoamine transporters or dopamine receptors in these studies.…”

Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice

“…In this regard, N -benzyl and N -(2-methoxy)benzyl substitution has been used to generate novel phenethylamines with further improved 5-HT 2A R binding affinity and functional activity in vitro (Braden et al, 2006) and in vivo (Halberstadt and Geyer, 2014), and further efforts with conformationally restricted N -benzylphenethylamines have resulted in the synthesis of an agonist compound with greater than 100-fold selectivity for 5-HT 2A R over 5-HT 2C R (Juncosa et al, 2013). Most recently, as part of larger efforts towards developing selective 5-HT 2A R agonists as PET ligands, 48 closely-related N -benzyl phenethylamines were evaluated as 5-HT 2A/2C R agonists (Hansen et al, 2014).…”

Re: Nye rusmidler rett fra nett

“…Some suppliers have therefore opted for selling it in the form of pre-loaded paper doses (blotters), similar to LSD 'tabs', so that users can take prepared dosage units, or as a spray (http://www.lizardlabs.co.uk/). The materials are potent hallucinogens, which act via the 5-HT2A receptors (Juncosa et al, 2013;Nichols et al, 2008), and so are probably regarded as alternatives to LSD. TheNBOMe compounds are reported to be inactivated if taken orally and so are usually taken by holding in the mouth (sub-lingual or buccal) or via the nasal membranes.…”