PHARMACOLOGICAL CHARACTERIZATION OF PD-152255, A NOVEL DIMERIC BENZIMIDAZOLE DOPAMINE D-3 ANTAGONIST

152255 (E-1,1'-(2-butene-1,4-diyl)bis (1-piperidinyl)propoxy]-phenyl]- 1H-benzimidazole]) exhibited high affinity (K-i = 12.7 nM) for human d opamine (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 huma n muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist acti vity at DA D-3 receptors was demonstrated by blockade of quinpirole-st imulated [H-3]-thymidine uptake in D-3 transfected cells, an effect th at was 28-fold more potent than in D-2-transfected cells. Unlike class ical DA D-2 antagonists, PD 152255 did not increase rat brain DA synth esis and it increased locomotion in habituated rats. However, like ant ipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rat s. These results demonstrate that PD 152255 is a DA D-3 antagonist tha t may have antipsychotic activity. (C) 1998 Elsevier Science Inc.