New Endomorphin Analogues Containing Alicyclic β-Amino Acids: Influence on Bioactive Conformation and Pharmacological Profile

• Published in: Journal of medicinal chemistry Vol. 51; no. 14; pp. 4270 - 4279
• Main Authors: Keresztes, Attila, Szűcs, Mária, Borics, Attila, Kövér, Katalin E, Forró, Enikő, Fülöp, Ferenc, Tömböly, Csaba, Péter, Antal, Páhi, Annamária, Fábián, Gabriella, Murányi, Mariann, Tóth, Géza
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.07.2008; Amer Chemical Soc
• Subjects: Amino Acids - chemistry; Animals; Biological and medical sciences; Chemistry, Medicinal; Life Sciences & Biomedicine; Male; Medical sciences; Molecular Conformation; Narcotic Antagonists; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nuclear Magnetic Resonance, Biomolecular; Opioid Peptides - chemistry; Opioid Peptides - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptors, Opioid - agonists; Receptors, Opioid - drug effects; Science & Technology; NEUROPATHIC PAIN; MORPHICEPTIN; PROTEIN SECONDARY STRUCTURE; NUCLEAR-MAGNETIC-RESONANCE; RAT-BRAIN; CARBOXYLIC-ACID; BINDING; MU-OPIOID RECEPTOR; PEPTIDE; AGONIST; Cyclohexane derivatives; Peptides; Rat; Endomorphin; Rodentia; Molecular dynamics method; Central nervous system; Theoretical study; Molecular interaction; Secondary structure; In vitro; Modeling; Opioid peptide; Biological activity; Vertebrata; Biological fixation; Mammalia; Tetrapeptide; Animal; Peptide synthesis; Solid phase; Chemical synthesis; Cyclopentane derivatives; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800223t

Endomorphins were subjected to a number of structural modifications in a search for their bioactive conformations. The alicyclic β-amino acids cis-(1S,2R)ACPC/ACHC, cis-(1R,2S)ACPC/ACHC, trans-(1S,2S)ACPC/ACHC, and trans-(1R,2R)ACPC/ACHC were introduced into endomorphins to examine the conformational effects on the bioactivity. Use of a combination of receptor binding techniques, 1H NMR, and molecular modeling allowed the conclusion that Pro2 substitution by these residues causes changes in structure, proteolytic stability, and pharmacological activity. It seems that the size of the alicyclic β-amino acids does not have marked influence on the receptor binding affinities and/or selectivities. Among the new analogues, the cis-(1S,2R)ACPC2 and cis-(1S,2R)ACHC2-containing derivatives displayed the highest binding potencies and efficacies in receptor binding and ligand-stimulated [35S]GTPγS functional experiments. Molecular dynamic simulations and 1H NMR studies of the cis-ACPC/ACHC-containing analogues revealed that many conformations are accessible, though it is most likely that these peptides bind to the μ-opioid receptor in a compact, folded structure rather than extended.