Influence of bulky 3,3′-diphenylalanine enantiomers replacing position 2 of AVP analogues on their conformations: NMR and molecular modeling studies

• Published in: European journal of medicinal chemistry Vol. 45; no. 9; pp. 4065 - 4073
• Main Authors: Sikorska, Emilia, Kwiatkowska, Anna, Sobolewski, Dariusz, Ślusarz, Rafał, Ślusarz, Magdalena J.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01.09.2010; Elsevier
• Subjects: 3,3-Diphenylalanine enantiomers; Amino Acid Sequence; Antiuterotonic activity; Arginine Vasopressin - analogs & derivatives; Arginine Vasopressin - chemistry; Arginine vasopressin analogues; Biological and medical sciences; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; NMR spectroscopy; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - chemistry; Phenylalanine - metabolism; Protein Conformation; Simulated annealing (SA); Stereoisomerism; V 2 agonists; Acc; V 2 agonists; 3,3-Diphenylalanine enantiomers; Dpa; OT; Antiuterotonic activity; Arginine vasopressin analogues; Simulated annealing (SA); GPCR; AVP; NMR spectroscopy; Mpa; Agonist; Cyclic peptides; 8-Arginine vasopressin; Peptide hormone; Molecular dynamics method; NMR spectrometry; Modeling; Neuropeptide; Antidiuretic hormone; Antidiuretic; Structure activity relation; Uterus; Enantiomer; V; Molecular model; V2 vasopressin receptor; Molecular rigidity; Theoretical study; Steric hindrance; Secondary structure; β-Structure; Muscle contraction; agonists; Conformation
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.05.066

In this paper we use NMR spectroscopy and molecular modeling to examine four vasopressin analogues substituted with bulky 3,3′-diphenylalanine (Dpa) enantiomers: [Mpa 1,Dpa 2,Val 4, d-Arg 8]VP ( I), [Mpa 1, d-Dpa 2,Val 4, d-Arg 8]VP ( II), [ d-Dpa 2, d-Arg 8]VP ( III) and [Mpa 1, d-Dpa 2]AVP ( IV). All the peptides exhibit a strong and prolonged antidiuretic activity. Additionally, analogues II, III and IV display antiuterotonic activity and analogue II is also a weak V 1a receptor blocker. The conformational analysis has shown that β-turns at positions 2,3 and/or 3,4 are characteristic of OT antagonists. In turn, the β-turn in the Cys 6-Gly 9 fragment seems to be crucial for enhancement of the antidiuretic activity. The high accessibility of aromatic side chains at positions 2 and 3 plays a crucial role in antagonist-receptor binding. Moreover, orientation of the Phe 3 side chain is claimed to be important for V 1a receptor affinity. [Display omitted]