Behavioral pharmacology of the gamma carboline Wy 47,384: A potential antipsychotic agent

Abstract

Wy 47,384 was examined in an extensive series of in vivo preclinical behavioral tests to determine its possible efficacy and side effect liability as a novel antipsychotic agent. Wy 47,384 was found to suppress avoidance responding following both i.p. and p.o. administration at doses that did not generally impair escape performance. Wy 47,384 also was found to be considerably more potent in antagonizing climbing behavior than stereotyped behavior produced by apomorphine. However, this compound demonstrated some cataleptogenic potential in catalepsy and global behavioral assessment tests. Wy 47,384 also produced limited sedation in motor activity, conflict, and rotorod ataxia tests, but the compound did not interact with ethanol. Wy 47,384 did not demonstrate preclinical anxiolytic activity in conflict behavior tests, and it did not show antidepressant effects in tests designed to assess beta‐adrenergic sensitivity. These studies show that Wy 47,384 is a specific putative antipsychotic agent with limited extrapyramidal and sedative side effect potential.

Discovery of Innovative Small Molecule Therapeutics

“…Both compounds demonstrated profiles in animal models of schizophrenia that suggested they might provide antipsychotic efficacy with reduced liabilities. For example, 1 and 2 blocked apomorphine-induced climbing in rats more potently than apomorphine-induced stereotypy and both compounds inhibited conditioned avoidance responding in rats and monkeys without inducing catalepsy. , Compounds 1 and 2 demonstrated antipsychotic activity in schizophrenic patients in phase II clinical trials. , An alternative approach that we pursued for balancing the paradoxical dopaminergic activity in the cortical and limbic systems was to identify D2 partial agonists . CoMFA-driven SAR studies directed toward discerning the D2 receptor agonist pharmacohore and topography identified two advanced series, the 7-hydroxyaminochromans (7-OH-AMC) and the 7-hydroxyaminobezodioxans (7-OH-AMB), and ultimately led to the discovery of the D2 partial agonist Aplindore (DAB-452, 3 ).…”

“…For example, 1 and 2 blocked apomorphine-induced climbing in rats more potently than apomorphine-induced stereotypy and both compounds inhibited conditioned avoidance responding in rats and monkeys without inducing catalepsy. 8,9 Compounds 1 and 2 demonstrated antipsychotic activity in schizophrenic patients in phase II clinical trials. 10,11 An alternative approach that we pursued for balancing the paradoxical dopaminergic activity in the cortical and limbic systems was to identify D2 partial agonists.…”