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 N,N-dialkyl derivatives (27-30) 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-1 and D-2 DA receptor subtypes by displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective). The amine 26 had about 2-fold less affinity for D-1 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-1 binding sites but greatly enhanced the effectiveness on D-2 binding sites. The N-ethyl- (28) and N-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 N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (31) which was approximately 65 times more selective for D-2 sites vs D-1 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.
Claudi
F
F
Department of Chemical Sciences, University of Camerino, Italy.
Cardellini
M
M
Cingolani
G M
GM
Piergentili
A
A
Peruzzi
G
G
Balduini
W
W
D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018492:Dopamine Antagonists; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D013329:Structure-Activity Relationship
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D010627:Phenethylamines; D011954:Receptors, Dopamine