Benzamide bioisosteres incorporating dihydroheteroazole substructures: EPC synthesis and SAR leading to a selective dopamine D4 receptor partial agonist (FAUC 179).
Conformationally restricted benzamide bioisosteres were investigated when the chiral phenyldihydroimidazole derivative 4e (FAUC 179) showed strong and highly selective dopamine D4 receptor binding (K(i)high=0.95nM). Mitogenesis experiments indicated partial agonist properties (42%). EPC syntheses of the target compounds of type 4 were performed starting from alpha-amino acids.
Einsiedel
J
J
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052, Erlangen, Germany.
Hübner
H
H
Gmeiner
P
P
D000818:Animals; D001671:Biochemistry / Q000379:methods; D016466:CHO Cells; D002417:Cattle; D003024:Clozapine / Q000494:pharmacology; D006224:Cricetinae; D003545:Cysteine / Q000737:chemistry; D018492:Dopamine Antagonists / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D012694:Serine / Q000737:chemistry; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013912:Threonine / Q000737:chemistry
C493599:DRD4 protein, human; D018492:Dopamine Antagonists; C448503:FAUC 179; D007211:Indoles; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D019257:Quinpirole; D013912:Threonine; D012694:Serine; D013134:Spiperone; D003024:Clozapine; D003545:Cysteine