Stereocontrolled dopamine receptor binding and subtype selectivity of clebopride analogues synthesized from aspartic acid.
Employing the achiral 4-aminopiperidine derivative clebopride as a lead compound, chiral analogues were developed displaying dopamine receptor binding profiles that proved to be strongly dependent on the stereochemistry. Compared to the D1 receptor, the test compounds showed high selectivity for the D2-like subtypes including D2(long), D2(short), D3 and D4. The highest D4 and D3 affinities were observed for the cis-3-amino-4-methylpyrrolidines 3e and the enantiomer ent3e resulting in K(i) values of 0.23 and 1.8 nM, respectively. The benzamides of type 3 and 5 were synthesized in enantiopure form starting from (S)-aspartic acid and its unnatural optical antipode.
Einsiedel
Jürgen
J
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Weber
Klaus
K
Thomas
Christoph
C
Lehmann
Thomas
T
Hübner
Harald
H
Gmeiner
Peter
P
D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism*; D001549:Benzamides / Q000138:chemical synthesis* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011954:Receptors, Dopamine / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
D001549:Benzamides; D011954:Receptors, Dopamine; D001224:Aspartic Acid; C014417:clebopride