Identification, characterization and pharmacological profile of three metabolites of (R)-(+)-1,2,3,6-tetrahydro-4-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 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.
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J L
JL
Wright
D M
DM
Downing
M R
MR
Feng
R N
RN
Hayes
T G
TG
Heffner
R G
RG
MacKenzie
L T
LT
Meltzer
T A
TA
Pugsley
L D
LD
Wise
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017660:Autoreceptors / Q000378:metabolism; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D012453:Saimiri
C097592:1,2,3,6-tetrahydro-4-(4-hydroxyphenyl)-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine; C097593:1,2,3,6-tetrahydro-4-(p-hydroxyphenyl)-1-((3-(p-hydroxyphenyl)-3-cyclohexen-1-yl)methyl)pyridine; D014150:Antipsychotic Agents; D017660:Autoreceptors; D018491:Dopamine Agonists; C094391:PD 147693; D011954:Receptors, Dopamine; C090025:1,2,3,6-tetrahydro-4-phenyl-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine