CI-1007, a dopamine partial agonist and potential antipsychotic agent. I. Neurochemical effects.
The receptor binding and biochemical effects of the putative dopamine (DA) partial agonist CI-1007 ([R(+)-1,2,3,6-tetrahydro-4-phenyl- 1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine] maleate) and potential antipsychotic were evaluated with a variety of biochemical methods. In receptor binding studies, CI-1007 bound to rat striatal DA receptors exhibiting a Ki of 3 nM as assessed by inhibition of [3H]N-propylnorapomorphine binding. CI-1007 also exhibited high affinity for cloned human D2L (Ki = 25.5 nM) and D3 (Ki = 16.6 nM) receptors with less affinity for D4.2 receptors (Ki = 90.9 nM). The affinity for serotonin-1A (5-HT-1A), alpha-2 adrenergic and 5-HT-2 receptors was moderate (submicromolar range) and slight or negligible for alpha-1, DA D1 and various other receptors. Unlike dopamine, the inhibition of [3H]spiperone binding was monophasic for CI-1007 and only slightly affected by the addition of Gpp-(NH)p. In vitro CI-1007 antagonized the forskolin-induced increases in cyclic AMP levels in GH4C1 cells expressing the human D2L receptor, having an intrinsic activity of 53% of that seen with the full agonist quinpirole. In vivo CI-1007 antagonized the gamma-butyrolactone (GBL)-induced accumulation of L-3,4-dihydroxyphenylalanine in striatum and mesolimbic regions of rat brain, causing a maximal 64% reversal in striatum, consistent with a partial agonist profile. In microdialysis studies it decreased DA overflow in both striatum and nucleus accumbens, indicating decreased release of DA. CI-1007 also reduced brain DA synthesis (DOPA accumulation), metabolism (DOPAC and HVA) and utilization (after tyrosine hydroxylase inhibition with alpha-methyl-p-tyrosine). CI-1007 did not affect striatal acetylcholine levels indicating lack of potent postsynaptic DA actions. CI-1007 seemed to be selective for DA neurons as it did not alter rat brain norepinephrine (NE) synthesis in the NE-enriched brainstem or NE utilization in the mesolimbic region. In addition, it did not affect in general 5-HT synthesis and metabolism in striatum and mesolimbic regions. These neurochemical results demonstrate that CI-1007 is a selective potent brain dopamine partial agonist with limited agonist activity at postsynaptic DA receptors.
Rugsley
T A
TA
Department of Neuroscience Pharmacology, Division of Warmer-Lambert Co., Ann Arbor, Michigan, USA.
Davis
M D
MD
Akunne
H C
HC
Cooke
L W
LW
Whetzel
S Z
SZ
MacKenzie
R G
RG
Shih
Y H
YH
van Leeuwen
D H
DH
DeMattos
S B
SB
Georgic
L M
LM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015107:4-Butyrolactone / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017660:Autoreceptors / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism
D014150:Antipsychotic Agents; D017660:Autoreceptors; D018491:Dopamine Agonists; D011954:Receptors, Dopamine; C090025:1,2,3,6-tetrahydro-4-phenyl-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine; D012701:Serotonin; D004295:Dihydroxyphenylalanine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000262:Adenylyl Cyclases; D000109:Acetylcholine; D015107:4-Butyrolactone; D004298:Dopamine