Pharmacological characterization of PD 152255, a novel dimeric benzimidazole dopamine D3 antagonist

152255 (E-1,1'-(2-butene-1,4-diyl)bis [2-[4-[3-(1-piperidinyl)propoxy]-phenyl]-1H-benzimidazole]) exhibited high affinity (K-i = 12.7 nM) for human dopamine (DA) D-3 receptors expressed in CHO K1 cells but not for DA D-2L receptors (K-i = 565 nM), DA D-4.2 or DA D-1 receptors (K-i > 3 mu M) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D-3 receptors was demonstrated by blockade of quinpirole-stimulated [H-3]-thymidine uptake in D-3 transfected cells, an effect that was 28-fold more potent than in D-2-transfected cells. Unlike classical DA D-2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D-3 antagonist that may have antipsychotic activity. (C) 1998 Elsevier Science Inc.