IDENTIFICATION, CHARACTERIZATION AND PHARMACOLOGICAL PROFILE OF 3 METABOLITES OF PHENYL-1-[(3-PHENYLCYCLOHEXEN-1-YL)METHYL]PYRIDINE (CI-1007), A DOPAMINE AUTORECEPTOR AGONIST AND POTENTIAL ANTIPSYCHOTIC AGENT())

Liquid chromatographic-mass spectrometric (LC-MS) analysis of plasma t aken from cynomolgus monkeys dosed orally with phenyl-1-[(3-phenylcycl ohexen-1-yl)methyl]pyridine (1), a dopamine (DA) autoreceptor agonist and potential antipsychotic agent, revealed several metabolites. The m olecular masses of three major metabolites suggested that they were mo no- and dihydroxylated derivatives of 1. We synthesized compounds 2 an d 3, the two possible mono-p-hydroxyphenyl derivatives of 1, along wit h the bis-p-hydroxyphenyl derivative 4. These compounds coeluted by HP LC with the three hydroxylated metabolites of 1. Compounds 2-4 all had high affinities for DA D2 and D3 receptors and moderate affinities fo r D4 receptors. Like 1, compound 2 decreased DA synthesis and neuronal firing in rat brain, indicative of DA autoreceptor activation. Compou nd 2 inhibited exploratory locomotor activity in rodents and was activ e in the Sidman avoidance test in squirrel monkeys, predictive of anti psychotic activity in humans. Compounds 3 and 4 showed weak activity i n all these tests. After squirrel monkeys were dosed with 1 orally at the ED(100) dose of the Sidman avoidance test, the plasma concentratio n of 2 was below the limit of quantitation. Therefore, these metabolit es are unlikely to contribute greatly to the potent activity seen with 1 in the Sidman avoidance test.