Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT_2A receptor agonists

Abstract

Experiments compared a series of phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT 2A receptors. The (±) phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol compared to their phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT 2A receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)-and (S)-phenylisopropylamines with their phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies.In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT 2A receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the receptor must be considered.

Extensive Rigid Analogue Design Maps the Binding Conformation of Potent N-Benzylphenethylamine 5-HT2A Serotonin Receptor Agonist Ligands

“…The residual dark yellow oil was purified by flash chromatography (EtOAc/ hexanes, 2:5) to give the product (2.85 g, 78%) as a colorless oil. The 3-(2,5-Dimethoxyphenyl)piperidine (20). A solution of 19 (0.924 g, 4.293 mmol) in 22 mL of AcOH was placed in a hydrogenation flask containing 0.097 g of PtO 2 , and the mixture was shaken under H 2 (50−70 psi) until TLC showed complete conversion (6 h).…”

Assessment of the Roles of Serines 5.43(239) and 5.46(242) for Binding and Potency of Agonist Ligands at the Human Serotonin 5-HT2AReceptor

“…Given sufficient sequence similarity/identity, the accuracy and reliability of comparative homology models is generally believed to be superior to de novo models (Baker and Sali, 2001) As an example of this approach, the in silico-activated homology model of the h5-HT 2A receptor developed in our laboratory has been used to predict several ligand-receptor interactions. Our results thus far have provided qualitative support for the model and have identified directions for further investigation of the structure-activity relationships of agonist ligands (Parrish et al, 2005;Braden et al, 2006;McLean et al, 2006a,b). Although such homology receptor models must be viewed with caution, they can often be validated by receptor mutagenesis experiments, along with complementary changes in ligand structure.…”

Structure–activity relationships of serotonin 5‐HT2A agonists

“…The R enantiomers were all about 50% more potent than the S enantiomers in the PI turnover assay. Parrish et al 91 also examined these compounds at the rat 5-HT 2A receptor, and although there were some minor differences, the overall trends were essentially the same. On the basis of molecular modeling studies, the authors speculated that in the R enantiomers, the α-methyl group interacted with Phe340 (6.52) through van der Waals interactions, as a possible explanation for the higher potency and intrinsic activity of these isomers.…”

“…60,[91][92][93] In a study by Parrish et al 91 the EC50s for stimulating phosphoinositide hydrolysis were nearly identical for phenethylamines and amphetamines, but the intrinsic activity was higher for the racemic amphetamines. For the amphetamine enantiomers, however, the affinity, potency, and intrinsic activity were significantly higher for the R-(−) enantiomer than for the S-(+) antipode.…”