title: Cyclic amidines as benzamide bioisosteres: EPC synthesis and SAR studies leading to the selective dopamine D4 receptor agonist FAUC 312.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: 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
chemical_list: 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