W. Kuipers et al., STUDY OF THE INTERACTION BETWEEN ARYLOXYPROPANOLAMINES AND ASN386 IN HELIX-VII OF THE HUMAN 5-HYDROXYTRYPTAMINE(1A) RECEPTOR, Molecular pharmacology, 51(5), 1997, pp. 889-896
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.