Chirospecific and subtype selective dopamine receptor binding of heterocyclic methoxynaphthamide analogs.
Employing the D(3) and D(4) selective methoxynaphthalines nafadotride and FAUC 182, respectively, as lead compounds, the pyrazolo[1,5-a]pyridine-3-carboxamides of type 1a and 2a as well as their 2-substituted regioisomers 1b and 2b were synthesized when following an ex-chiral pool approach. Dopamine receptor binding studies involving the target compounds (1a,b, 2a,b) and the respective optical antipodes ent-1a,b and ent-2a,b revealed the heterocyclic carboxamide 2a as a strong and selective D(4) ligand (K(i) = 8.6 nM). According to a mitogenesis assay, 2a shows D(4) partial agonist effects (29%, EC(50) = 6.7 nM) and, thus, might be of interest for the treatment of sexual dysfunction.
Bettinetti
Laura
L
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
Hübner
Harald
H
Gmeiner
Peter
P
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods; D009281:Naphthalenes / Q000378:metabolism* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011954:Receptors, Dopamine / Q000145:classification / Q000187:drug effects*; D020018:Sexual Dysfunctions, Psychological / Q000188:drug therapy; D013134:Spiperone / Q000494:pharmacology; D013237:Stereoisomerism; D013469:Sulpiride / Q000494:pharmacology; D013552:Swine; D013936:Thymidine / Q000494:pharmacology; D014316:Tritium
D001552:Benzazepines; D006571:Heterocyclic Compounds; D009281:Naphthalenes; D011720:Pyrazoles; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D014316:Tritium; D013134:Spiperone; D013469:Sulpiride; D013936:Thymidine