Bicyclic thiazolidine lactam peptidomimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2.
Bicyclic thiazolidine lactam peptidomimetics 3-5 have been synthesized as potential analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2 (PLG). Peptidomimetics 3 and 4 were designed to constrain two, psi 2 and phi 3, of the four torsion angles that define a beta-turn to values approximating those found for a type-II beta-turn, while 5 was designed as a compound that could not achieve a beta-turn conformation. Peptidomimetics 3 and 4 were found to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor, while 5 was found to be inactive. Like PLG the dose-response curves for 3 and 4 were bell-shaped in nature with the maximum effect occurring at a concentration of 1 microM. Both 3 and 4 were more effective than PLG in enhancing the binding of ADTN to dopamine receptors. The 5,5-bicyclic thiazolidine lactam peptidomimetic 3 enhanced the binding of ADTN by almost 200%, while the 6,5-bicyclic thiazolidine lactam peptidomimetic 4 enhanced the binding of ADTN by about 75%. These results provide further evidence in support of the hypothesis that the bioactive conformation of PLG is a type-II beta-turn.
Subasinghe
N L
NL
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Bontems
R J
RJ
McIntee
E
E
Mishra
R K
RK
Johnson
R L
RL
D000818:Animals; D002417:Cattle; D015259:Dopamine Agents / Q000378:metabolism*; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D015259:Dopamine Agents; D007769:Lactams; D010455:Peptides; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; C011639:ADTN; D009075:MSH Release-Inhibiting Hormone