STUDY OF THE INTERACTION BETWEEN ARYLOXYPROPANOLAMINES AND ASN386 IN HELIX-VII OF THE HUMAN 5-HYDROXYTRYPTAMINE(1A) RECEPTOR

We studied the stereoselective interaction between aryloxypropanolamin es and the human 5-hydroxytryptamine(1A) (5-HT1A ) receptor. R- and S- enantiomers of propranolol, penbutolol, and alprenolol were investigat ed for their ability to bind to human 5-HT1A wild-type and Asn386Val m utant receptors. Asn386 seemed to act as a chiral discriminator. Altho ugh both aryloxypropanol enantiomers displayed lower affinity for the mutant receptors, the affinities for the S-enantiomers were more affec ted. Receptor affinities of other structurally unrelated 5-HT1A ligand s were not decreased by the mutation of Asn386 to valine. In addition, a series of analogues of propranolol with structural variation in the oxypropanolamine moiety was synthesized, and affinities for wild-type and Asn386Val mutant 5-HT1A receptors were determined. Both the hydro xyl and the ether oxygen atoms of the oxypropanol moiety seem to be re quired for binding at wild-type 5-HT1A receptors. The hydroxyl group o f propranolol probably directly interacts with Asn386. The ether oxyge n atom may be important for steric reasons but can also be involved in a direct interaction with Asn386. These findings are in agreement wit h the interactions of aryloxypropanolamines with Asn386 in rat 5-HT1A receptors that we previously proposed. The loss of affinity for propra nolol by the Asn386Val mutation could be regained by replacement of th e hydroxyl group of the ligand by a methoxy group. This modification o f the propranolol structure has no effect on the affinity of both enan tiomers for the wild-type 5-HT1A receptor, which provides an alternati ve hypothesis for the interaction of Asn386 with the oxypropanol oxyge n atoms. According to this novel hypothesis, the oxypropanol oxygen at oms may both act as hydrogen bond accepters from the NH2 group of Asn3 86.