Pharmacological Characterization of PD 152255, a Novel Dimeric Benzimidazole Dopamine D3 Antagonist

Abstract 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 μ 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 [ 3 H]-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.