Effects of Modifications of Residues in Position 3 of Dynorphin A(1−11)-NH2 on κ Receptor Selectivity and Potency

• Published in: Journal of medicinal chemistry Vol. 39; no. 13; pp. 2456 - 2460
• Main Authors: Lung, Feng-Di T, Meyer, J.-P, Lou, Bih-Show, Xiang, Li, Li, Guigen, Davis, Peg, De Leon, Irene A, Yamamura, Henry I, Porreca, Frank, Hruby, Victor J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 21.06.1996
• Subjects: Amino Acid Sequence; Analgesics - pharmacology; Animals; Benzeneacetamides; Biological and medical sciences; Brain - metabolism; Dynorphins - chemistry; Dynorphins - metabolism; Enkephalin, Ala-MePhe-Gly; Enkephalins - pharmacology; Guinea Pigs; Ileum - drug effects; Medical sciences; Molecular Sequence Data; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Binding; Protein Conformation; Pyrrolidines - pharmacology; Receptors, Opioid - metabolism; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Structure-Activity Relationship; Oligopeptides; Ligand; Rodentia; Central nervous system; Gut; Smooth muscle; Dynorphin A; Selectivity; Ileum; In vitro; Opioid peptide; Opiate receptor κ; Vertebrata; Biological fixation; Chemical modification; Mammalia; Guinea pig; Structure activity relation; Animal; Affinity; Peptide synthesis; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950655o

Tyrosine and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at κ receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [d-Ala3]Dyn A(1−11)-NH2 (2) and [Ala3]Dyn A(1−11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central κ opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1−11)-NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for κ vs μ and κ vs δ receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1−11)-NH2 as well as the conformational changes they induce in the message sequence of dynorphin have important effects on potency and selectivity for κ opioid receptors. To further investigate structure−activity relationships involving the residue at the 3 position of Dyn A(1−11)-NH2, a series of Dyn A analogues with aromatic, charged, and aliphatic side chain substitutions at the 3 position was designed, synthesized, and evaluated for their affinities for κ, μ, and δ opioid receptors. It was found that analogues with lipophilic amino acids at the 3 position of Dyn A(1−11)-NH2 generally displayed higher affinity but similar selectivities for the κ receptor than analogues with charged residues at the same position. It is suggested that the structural, configurational, and steric/lipophilic effects of amino acids at position 3 of Dyn A(1−11)-NH2 may play an important role in potency and selectivity for the κ receptor.