Nafadotride, a potent preferential dopamine D3 receptor antagonist, activates locomotion in rodents

Nafadotride (N[(n-butyl-2-pyrrolidinyl)methyl]-1-methoxy-4-cyano naphtalene-2-carboxamide) is a novel compound, which inhibits potently and stereoselectively [125I]iodosulpride binding at recombinant human dopamine D3 receptors. the levoisomer displays an apparent Ki value of 0.3 nM at the dopamine D3 receptor, but is 10 times less potent at the human recombinant dopamine D2 receptor. In comparison, the dextroisomer displays 20-fold less apparent affinity at the dopamine D3 receptor and reduced (2-fold) selectivity. l-Nafadotride displays iow, micromolar affinity at dopamine D1 and D4 receptors and negligible apparent affinity at various other receptors. In dopamine D3 receptor-transfected NG-108 15 cells, in which dopamine agonists increase mitogenesis, l-nafadotride has no intrinsic activity, but competitively antagonizes the quinpirole-induced mitogenetic response, monitored by [3H]thymidine incorporation with a pA2 of 9.6. In dopamine D2 receptor-transfected Chinese Hamster Ovary cells, l-nafadotride also behaves as a competitive antagonist of quinpirole-induced mitogenesis with an 11-fold lower potency. These studies establish nafadotride as a pure, extremely potent, competitive and preferential dopamine D3 receptor antagonist in vitro. l-Nafadotride displaces in vivo N-[3H]propylnorapomorphine accumulation at lower dosage and for longer periods in limbic structures, containing both dopamine D2 and D3 receptors than in the stratum, containing dopamine D2 receptor only. At low dosage (0.1-1 mg/kg), nafadotride, unlike haloperidol, a dopamine D2 receptor-preferring antagonist, increases spontaneous locomotion of habituated rats and climbing behavior of mice, at doses that do not modify striatal homovanillic acid levels. At high dosage (1-100 mg/kg), nafadotride, like haloperidol, produces catalepsy and antagonizes apomorphine-induced climbing.(ABSTRACT TRUNCATED AT 250 WORDS)