Pharmacology - Molecular Interaction of Serotonin 5-HT2A Receptor Residues Phe339(6.51) and Phe340(6.52) with Superpotent N-Benzyl Phenethylamine Agonists

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Description:
From the Nichols group:

ABSTRACT
Experiments were conducted to examine the molecular basis
for the high affinity and potency of a new class of 5-HT2A
receptor agonists, N-benzyl phenethylamines. Competition
binding assays at several serotonin receptors confirmed that an
N-arylmethyl substitution was necessary for affinity increases
up to 300-fold over simple N-alkyl homologs, as well as enhanced
selectivity for 5-HT2A versus 5-HT2C and 5-HT1A receptors.
PI hydrolysis functional assays confirmed that these Nbenzyl
phenethylamines are potent and highly efficacious
agonists at the rat 5-HT2A receptor. Virtual docking of these
compounds into a human 5-HT2A receptor homology model
indicated that the N-benzyl moiety might be interacting with
Phe339(6.51), whereas the phenethylamine portion was likely to
be interacting with Phe340(6.52). Experiments in h5-HT2A receptors
with Phe339(6.51)L and Phe340(6.52)L mutations seem to
support this hypothesis. Dramatic detrimental effects on affinity,
potency, and intrinsic activity were observed with the
Phe339(6.51)L mutation for all N-benzyl analogs, whereas most
N-unsubstituted phenethylamines and traditional agonists were
only weakly affected, if at all. Consistent with other published
studies, the Phe340(6.52)L mutation detrimentally affected affinity,
potency, and intrinsic activity of nearly all compounds
tested, although a strong change in intrinsic activity was not
seen with most N-aryl analogs. These data further validate the
topology of our h5-HT2A receptor homology model. It is noteworthy
that this study is the first to identify a hitherto unrecognized
role for residue 6.51 in agonist activation of a serotonin G
protein-coupled receptor (GPCR), whereas most previous reports
have suggested a varied and sometimes contradictory
role in homologous GPCRs.

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Any one read this guy?