Cyclic amidines as benzamide bioisosteres: EPC synthesis and SAR studies leading to the selective dopamine D4 receptor agonist FAUC 312.
Investigation of conformationally restricted benzamide bioisosteres led to the chiral phenyltetrahydropyrimidine derivative ent2a (FAUC 312) displaying strong and highly selective dopamine D4 receptor binding (K(i(high))=1.5 nM). Mitogenesis experiments indicated 83% ligand efficacy when compared to the unselective agonist quinpirole. The target compounds of type 2 and 3 were synthesized in enantiopure form starting from asparagine.
Einsiedel
Jürgen
J
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Hübner
Harald
H
Gmeiner
Peter
P
D000578:Amidines / Q000737:chemistry*; D000818:Animals; D001549:Benzamides / Q000737:chemistry*; D016466:CHO Cells; D002417:Cattle; D003024:Clozapine / Q000494:pharmacology; D006224:Cricetinae; D003500:Cyclization; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008934:Mitogens / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000578:Amidines; D001549:Benzamides; C493599:DRD4 protein, human; C478148:FAUC 312; D008024:Ligands; D008934:Mitogens; D010879:Piperazines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D019257:Quinpirole; C037689:benzamide; D003024:Clozapine