Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors

Paul Taylor,Vignir Isberg,Jesper L Kristensen,David E Gloriam,Sebastian Leth-Petersen,James Paine

doi:10.1371/journal.pone.0078515

Abstract

Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9–11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9–11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9–11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

Highlights

The 5-HT2 subfamily consists of the three subtypes, serotonin receptors 2A-C (5-HT2A-C). 5-HT2A inhibition by clinical drugs has antipsychotic and antidepressive effects.[10] 5-HT2A subtype stimulation by full or partial agonists mediates the hallucinogenic effects of many natural and synthetic drugs.[1,11,12]
There is a clinical need for more highly 5-HT2 subtype-selective ligands and the most attention has been given to the phenethylamine class
The phenethylamine ligand 2C-B (1a in Fig. 1) contains the structural features required for hallucinogenic activity; a primary amine separated from the phenyl ring by two carbon atoms, 2- and 5-aromatic methoxy groups, and a hydrophobic 4-substituent

Summary

Introduction

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has key roles in mood, libido, aggression, anxiety, cognition, sleep, appetite and pain and regulates peripheral functions in the cardiovascular, gastrointestinal, endocrine and pulmonary system.[1,2,3,4] Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders.[1,5,6,7,8,9] The serotonergic system comprises 12 Class A G protein-coupled receptors and one ligand-gated ion channel that together are divided into 7 pharmacological subfamilies. The 5-HT2 subfamily consists of the three subtypes, serotonin receptors 2A-C (5-HT2A-C). 5-HT2A inhibition by clinical drugs has antipsychotic (e.g., clozapine) and antidepressive (e.g., mianserin) effects.[10] 5-HT2A subtype stimulation by full or partial agonists mediates the hallucinogenic effects of many natural (e.g. psilocybin and mescaline) and synthetic drugs.[1,11,12]. The 5-HT2A agonist structures generally fall into one of three categories, phenethylamines, tryptamines and ergolines.[13] There is a clinical need for more highly 5-HT2 subtype-selective ligands and the most attention has been given to the phenethylamine class. The phenethylamine ligand 2C-B (1a in Fig. 1) contains the structural features required for hallucinogenic activity; a primary amine separated from the phenyl ring by two carbon atoms, 2- and 5-aromatic methoxy groups, and a hydrophobic 4-substituent. Methylation of the amine a-carbon, as in DOB (1b), DOB-fly (2b) and DOB-butterfly (3b), results in slightly decreased in vitro affinities but increases the strength and duration of the response in vivo – hypothesized to be a consequence of increased metabolic stability resulting in higher exposure.[14]

Methods

Results

Conclusion