SYNTHESIS AND DOPAMINE RECEPTOR AFFINITIES OF 2-(4-FLUORO-3-HYDROXYPHENYL)ETHYLAMINE AND N-SUBSTITUTED DERIVATIVES

The synthesis of 2-(4-fluoro-3-hydroxyphenyl)ethylamine (26) and of some A^TV-dialkyl derivatives (27–36) starting from 4-fluoro-3-hydroxytoluene and their in vitro binding affinities for dopamine (DA) receptor are reported. The amine 26 can be regarded as a molecular modification of DA in which the para hydroxyl group is replaced by fluorine. The new compounds 26–30 were evaluated for their affinity at D-l and D-2 DA receptor subtypes by displacement of [3H]SCH 23390 (D-l selective) and [3H]spiperone (D-2 selective). The amine 26 had about 2-fold less affinity for D-l and D-2 binding sites than DA. The substitution of the amino group with ethyl, n-propyl, and 2-phenylethyl groups decreased the affinity for D-l binding sites but greatly enhanced the effectiveness on D-2 binding sites. The N-ethyl- (28) and AT-n-propyl-.N-(2-phenylethyl)-2-(4-fluoro-3-hydroxyphenyl)ethylamine (30) were the most potent members of the series with high selectivity for D-2 binding sites. A similar effect was observed with isomeric,V-n-propyl-Ar-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (31) which was approximately 65 times more selective for D-2 sites vs D-l sites, The introduction of a 2-phenylethyl group on the nitrogen atom induce the highest effect, perhaps as a consequence of an increased liposolubility or of binding to a complementary lipophilic site on the receptor. © 1990, American Chemical Society. All rights reserved.