NG-Acyl-argininamides as NPY Y1 receptor antagonists: Influence of structurally diverse acyl substituents on stability and affinity

NG-Acylated argininamides, covering a broad range of lipophilicity (calculated log D values: −1.8–12.5), were synthesized and investigated for NPY Y1 receptor (Y1R) antagonism, Y1R affinity and stability in buffer (NG-deacylation, yielding BIBP 3226). Broad structural variation of substituents was tolerated. The Ki (binding) and Kb values (Y1R antagonism) varied from low nM to one-digit μM. Most of the compounds proved to be sufficiently stable at pH 7.4 over 90 min to determine reliable pharmacological data in vitro. Exceptionally high instability was detected when a succinyl moiety was attached to the guanidine, probably, due to an intramolecular cleavage mechanism.

Figure optionsDownload as PowerPoint slide