Design, Synthesis, Pharmacological Evaluation, and Structure−Activity Study of Novel Endomorphin Analogues with Multiple Structural Modifications

• Published in: Journal of medicinal chemistry 2011-03, Vol.54 (5), p.1462-1472
• Main Authors: Mallareddy, Jayapal Reddy, Borics, Attila, Keresztes, Attila, Kövér, Katalin E, Tourwé, Dirk, Tóth, Géza
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Animals; Brain - metabolism; Drug Stability; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Hydrolysis; In Vitro Techniques; Ligands; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Molecular Conformation; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptors, Opioid, mu - agonists; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm101515v

This study reports on new proteolytically stable, pharmacologically active endomorphin analogues, incorporating Dmt1, Achc2, pFPhe4, or βMePhe4 unnatural amino acids. Consistent with earlier results, it was found that the analogues carrying Dmt1 and Achc2 residues displayed the highest μ-opioid receptor affinities, depending upon the configuration of the incorporated Achc2. Combination of such derivatives with pFPhe4 or βMePhe4 yielded further compounds with variable binding potencies. Combined application of Dmt1, cis-(1S,2R)Achc2, and pFPhe4 (compound 16) resulted in the most potent analogue. Ligand stimulated [35S]GTPγS binding assays indicated that the analogues retained their agonist activities and opioid receptor specificities. NMR and molecular modeling studies of the analogues containing βMePhe4 or pFPhe4 confirmed the predominance of bent structures, however, it is apparent that bent structures are energetically more favored than random/extended structures for all studied compounds.