Structure-affinity relationships of halogenated predicentrine and glaucine derivatives at D1 and D2 dopaminergic receptors:: halogenation and D1 receptor selectivity

Halogenation of the aporphine alkaloid boldine at the 3-position leads to increased affinity for rat brain D-1-like dopaminergic receptors with some selectivity over D-2-like receptors. A series of 3-halogenated and 3,8-dihalogenated (halogen = Cl, Br or 1) derivatives of predicentrine (9-O-methylboldine) and glaucine (2,9-di-O-methylboldine) were prepared and assayed for binding at D-1 and D-2 sites. Halogenation of predicentrine led to strong increases in affinity for D-1-like receptors, while the affinities for D-2-like receptors were either practically unchanged or reduced three- to fourfold. Halogenated glaucine derivatives did not show any clear trend towards enhanced selectivity, and the affinities were poor and similar to or worse than the values previously recorded for glaucine itself. Together with earlier work on boldine derivatives, these results suggest that the 2-hydroxy group on the aporphine skeleton may determine a binding mode favoring D-1-like over D-2-like receptors, with enhanced affinity when the C-3 position is halogenated. (c) 2005 Elsevier Ltd. All rights reserved.