NGD 94-I: A Specific Dopamine-4-Receptor Antagonist

Publisher Summary

NGD 94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole dimaleate) is a highly selective agent at the D4 receptor—a D4 antagonists. NGD 94-1 possesses a preclinical profile that is at once similar to clozapine and also quite different from clozapine. Its affinity for D4 receptors is 3 nM, while its affinity at D1, D2, D3, and D5 receptors is greater than 2 pM, NGD 94-1 has no significant affinity for a wide variety of monoamine or other neurotransmitter receptor or modulatory sites. The only other significant receptor activity is found at 5HT1A receptors with an affinity of 180 nM. The nonspecific agonist, quinpirole, is a specific D4 agonist and inhibits forskolin-stimulated adenylate cyclase activity in a cell line stably expressing only D4 receptors. NGD 94-1 inhibits this agonist effect of quinpirole without possessing significant agonist activity of its own. Thus, NGD 94-1 appears to be a D4 receptor antagonist in this system. In direct binding experiments, [³H]NGD 94-1, prepared by the reductive tritiation of a halogenated precursor, binds to a single set of receptors in transformed cells expressing the human D4 receptor. The pharmacological binding profile of [³H]NGD 94-1 is consistent with expected D4 pharmacology.