2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist.
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.
Enguehard-Gueiffier
Cécile
C
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 31 avenue Monge, F-37200 Tours, France.
Hübner
Harald
H
El Hakmaoui
Ahmed
A
Allouchi
Hassan
H
Gmeiner
Peter
P
Argiolas
Antonio
A
Melis
Maria Rosaria
MR
Gueiffier
Alain
A
D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D007172:Erectile Dysfunction / Q000188:drug therapy; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008938:Mitosis / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D050638:Receptors, Dopamine D4 / Q000819:agonists* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
C512440:2-(4-(2-methoxyphenyl)piperazin-1-ylmethyl)imidazo(1,2-a)pyridine; C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D007093:Imidazoles; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D011758:Pyrroles; D050638:Receptors, Dopamine D4; D016244:Guanosine 5'-O-(3-Thiotriphosphate)