Abstract
A series of novel 2-[(4-phenylpiperazin-1-yl)methyl]imidazoazines and aza-analogues were prepared and screened at selected dopamine, serotonin, and adrenergic receptor subtypes. 2-Substituted imidazopyridines and pyridazines presented high affinities and selectivities for D4 dopamine receptors. Whereas functional experiments indicated neutral antagonists or weak partial agonist effects for most of the target compounds, the 2-methoxyphenyl substituted 2-piperazinylmethylimidazopyridine 3c (PIP3EA) displayed substantial agonist efficacy in mitogenesis experiments and GTPgammaS binding tests, resulting in EC50 values of 3.0 (46%) and 4.5 nM (57%), respectively. Our D4 agonist 3c induced penile erection in vivo when administered to rats. This effect was inhibited by L-745,870 a D4 selective antagonist, confirming the mechanistic pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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Cattle
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Cricetinae
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Cricetulus
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Erectile Dysfunction / drug therapy
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Ligands
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Male
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Mitosis / drug effects
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Penile Erection / drug effects
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyrroles / pharmacology
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Radioligand Assay
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Rats
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Receptors, Dopamine D4 / agonists*
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Receptors, Dopamine D4 / antagonists & inhibitors
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Structure-Activity Relationship
Substances
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2-(4-(2-methoxyphenyl)piperazin-1-ylmethyl)imidazo(1,2-a)pyridine
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3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine
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Imidazoles
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Ligands
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Piperazines
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Pyridines
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Pyrroles
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Receptors, Dopamine D4
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Guanosine 5'-O-(3-Thiotriphosphate)