Design of selective peptidomimetic agonists for the human orphan receptor BRS-3.
New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay. Focusing on the N-terminus, the d-Phe-Gln moiety of 4 was modified in a combinatorial SAR-oriented medicinal chemistry approach. With the incorporation of N-arylated glycine and alanine building blocks azaglycine, piperazine, or piperidine and the synthesis of semicarbazides and semicarbazones, a number of highly potent and selective compounds with a reduced number of peptide bonds were obtained, which also should have enhanced metabolic stability.
Weber
Dirk
D
Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Berger
Claudia
C
Eickelmann
Peter
P
Antel
Jochen
J
Kessler
Horst
H
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D006801:Humans; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D018004:Receptors, Bombesin / Q000819:agonists* / Q000037:antagonists & inhibitors; D012663:Semicarbazides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012664:Semicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D009842:Oligopeptides; D010455:Peptides; D018004:Receptors, Bombesin; D012663:Semicarbazides; D012664:Semicarbazones; C107120:bombesin receptor subtype 3; C474571:phenylalanyl-glutaminyl-tryptophan 1-(2-phenylethyl)amide; D002118:Calcium