NAFADOTRIDE, A POTENT PREFERENTIAL DOPAMINE D-3 RECEPTOR ANTAGONIST, ACTIVATES LOCOMOTION IN RODENTS

Nafadotride [(n-butyl-2-pyrrolidinyl)methyl]-1-methoxy-4-cyano naphtal ene-2-carboxamide} is a novel compound, which inhibits potently and st ereoselectively [I-125]iodosulpride binding al recombinant human dopam ine D-3 receptors. The levoisomer displays an apparent K-i value of 0. 3 nM at the dopamine D-3 receptor, but is 10 times less potent at the human recombinant dopamine D-2 receptor. In comparison, the dextroisom er displays 20-fold less apparent affinity at the dopamine D-3 recepto r and reduced (2-fold) selectivity. I-Nafadotride displays low, microm olar affinity at dopamine D-1 and D-4 receptors and negligible apparen t affinity at various other receptors. In dopamine D-3 receptor-transf ected NG-108 15 cells, in which dopamine agonists increase mitogenesis , I-nafadotride has no intrinsic activity, but competitively antagoniz es the quinpirole-induced mitogenetic response, monitored by [H-3]thym idine incorporation with a pA(2), of 9.6. In dopamine D-2 receptor-tra nsfected Chinese Hamster Ovary cells, I-nafadotride also behaves as a competitive antagonist of quinpirole-induced mitogenesis with an Ii-fo ld lower potency. These studies establish nafadotride as a pure, extre mely potent, competitive and preferential dopamine D-3 receptor antago nist in vitro. I-Nafadotride displaces in vivo N-[H-3]propylnorapomorp hine accumulation at lower dosage and for longer periods in limbic str uctures, containing both dopamine D-2 and D-3 receptors than in the st riatum, containing dopamine D, receptor only. At low dosage (0.1-1 mg/ kg), nafadotride, unlike haloperidol, a dopamine D-2 receptor-preferri ng antagonist, increases spontaneous locomotion of habituated rats and climbing behavior of mice, at doses that do not modify striatal homov anillic acid levels. At high dosage (1-100 mg/kg), nafadotride, like h aloperidol, produces catalepsy and antagonizes apomorphine-induced cli mbing. These data suggest that dopamine D, receptor blockade results i n motor activation, contrasting with the motor sedation caused by clas sical antagonists with a dopamine D-2 receptor preference, like halope ridol.