Identification, Characterization and Pharmacological Profile of Three Metabolites of (R)-(+)-1,2,3,6-Tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1-yl)methyl]p yridine (CI-1007), a Dopamine Autoreceptor Agonist and Potential Antipsychotic Agent

Citations Over Time

Abstract

Liquid chromatographic-mass spectrometric (LC-MS) analysis of plasma taken from cynomolgus monkeys dosed orally with (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1- yl)methyl]pyridine (1), a dopamine (DA) autoreceptor agonist and potential antipsychotic agent, revealed several metabolites. The molecular masses of three major metabolites suggested that they were mono- and dihydroxylated derivatives of 1. We synthesized compounds 2 and 3, the two possible mono-p-hydroxyphenyl derivatives of 1, along with the bis-p-hydroxyphenyl derivative 4. These compounds coeluted by HPLC with the three hydroxylated metabolites of 1. Compounds 2-4 all had high affinities for DA D2 and D3 receptors and moderate affinities for D4 receptors. Like 1, compound 2 decreased DA synthesis and neuronal firing in rat brain, indicative of DA autoreceptor activation. Compound 2 inhibited exploratory locomotor activity in rodents and was active in the Sidman avoidance test in squirrel monkeys, predictive of antipsychotic activity in humans. Compounds 3 and 4 showed weak activity in all these tests. After squirrel monkeys were dosed with 1 orally at the ED100 dose of the Sidman avoidance test, the plasma concentration of 2 was below the limit of quantitation. Therefore, these metabolites are unlikely to contribute greatly to the potent activity seen with 1 in the Sidman avoidance test.

Related Papers

• → The role of D2-autoreceptors in regulating dopamine neuron activity and transmission(2014)601 cited
• → Preferential Enhancement of Dopamine Transmission within the Nucleus Accumbens Shell by Cocaine Is Attributable to a Direct Increase in Phasic Dopamine Release Events(2008)231 cited
• → Methamphetamine produces bidirectional, concentration-dependent effects on dopamine neuron excitability and dopamine-mediated synaptic currents(2012)71 cited
• → Central α₂‐autoreceptors: agonist dissociation constants and recovery after irreversible inactivation(1993)14 cited
• → Dopamine release and metabolism after chronic delivery of selective or nonselective dopamine autoreceptor agonists.(1988)8 cited