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MOLECULAR PHARMACOLOGY 51:889-896 (1997).

Study of the Interaction Between Aryloxypropanolamines and Asn386 in Helix VII of the Human 5-Hydroxytryptamine_1A Receptor

Wilma Kuipers, Regina Link, Piet J. Standaar, Axel R. Stoit, Ineke Van Wijngaarden, Rob Leurs, and Adriaan P. Ijzerman

Department of Medicinal Chemistry, Solvay Pharmaceuticals Research Laboratories, 1380 DA Weesp, The Netherlands (W.K., P.J.S., A.R.S., I.v.W.), Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden, The Netherlands (R. Link., A.P.I.J.); and Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, 1081 HV Amsterdam, The Netherlands (R. Leurs.).

We studied the stereoselective interaction between aryloxypropanolamines and the human 5-hydroxytryptamine_1A (5-HT_1A) receptor. R- and S-enantiomers of propranolol, penbutolol, and alprenolol were investigated for their ability to bind to human 5-HT_1A wild-type and Asn386Val mutant receptors. Asn386 seemed to act as a chiral discriminator. Although both aryloxypropanol enantiomers displayed lower affinity for the mutant receptors, the affinities for the S-enantiomers were more affected. Receptor affinities of other structurally unrelated 5-HT_1A ligands 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-HT_1A receptors were determined. Both the hydroxyl and the ether oxygen atoms of the oxypropanol moiety seem to be required for binding at wild-type 5-HT_1A receptors. The hydroxyl group of propranolol probably directly interacts with Asn386. The ether oxygen atom may be important for steric reasons but can also be involved in a direct interaction with Asn386. These findings are in agreement with the interactions of aryloxypropanolamines with Asn386 in rat 5-HT_1A receptors that we previously proposed. The loss of affinity for propranolol by the Asn386Val mutation could be regained by replacement of the hydroxyl group of the ligand by a methoxy group. This modification of the propranolol structure has no effect on the affinity of both enantiomers for the wild-type 5-HT_1A receptor, which provides an alternative hypothesis for the interaction of Asn386 with the oxypropanol oxygen atoms. According to this novel hypothesis, the oxypropanol oxygen atoms may both act as hydrogen bond acceptors from the NH₂ group of Asn386.