1656045

pubmed:Citation

10

In an effort to determine the effect of side chain conformational restriction on opioid receptor selectivity, the cyclic phenylalanine analogues 2-aminoindan-2-carboxylic acid (Aic), 2-aminotetralin-2-carboxylic acid (Atc), and tetrahydroisoquinoline-3-carboxylic acid (Tic) were substituted for Phe in the potent cyclic opioid peptide analogue H-Tyr-D-Orn-Phe-Glu-NH2, which lacks significant opioid receptor selectivity. Compounds were tested in mu- and delta-opioid receptor representative binding assays and bioassays in vitro. The analogue H-Tyr-D-Orn-Aic-Glu-NH2 was found to be a potent agonist with high preference of mu receptors over delta receptors. Opening of the five-membered ring of Aic in the latter peptide, as achieved through substitution of C alpha-methylphenylalanine or o-methylphenylalanine, resulted in only slightly selective compounds, indicating that the high mu selectivity of the Aic analogue is exclusively the consequence of the imposed side chain conformational restriction. Both diastereoisomers of H-Tyr-D-Orn-(D,L)-Atc-Glu-NH2 were highly mu-selective and, in contrast to the weak affinity observed with the D-Phe3 analogue as compared to the L-Phe3 analogue, both had similar potency. Thus, stereospecificity was lost as a consequence of side chain conformational restriction. Further structure-activity data obtained with analogues containing L- or D-homophenylalanine (Hfe) or 3-(1'-naphthyl)alanine (Nap) in place of Phe3 and consideration of geometric interrelationships between Nap and the L and D isomers of Atc, Hfe, and Phe led to the proposal that the D-Phe3 and the D-Atc3 analogue may have different modes of binding to the receptor. The very low potency observed with H-Tyr-D-Orn-N alpha MePhe-Glu-NH2 (N alpha MePhe = N alpha-methylphenylalanine) and H-Tyr-D-Orn-Tic-Glu-NH2 indicated that N alpha-alkylation at the 3-position is detrimental to activity.

eng

IM

MEDLINE

0022-2623

Print

NLM

3125-32

pubmed-meshheading:1656045-Amino Acid Sequence, pubmed-meshheading:1656045-Animals, pubmed-meshheading:1656045-Biological Assay, pubmed-meshheading:1656045-Brain, pubmed-meshheading:1656045-Cell Membrane, pubmed-meshheading:1656045-Cyclization, pubmed-meshheading:1656045-Endorphins, pubmed-meshheading:1656045-Guinea Pigs, pubmed-meshheading:1656045-Indans, pubmed-meshheading:1656045-Isoquinolines, pubmed-meshheading:1656045-Mice, pubmed-meshheading:1656045-Molecular Conformation, pubmed-meshheading:1656045-Molecular Sequence Data, pubmed-meshheading:1656045-Muscle, Smooth, pubmed-meshheading:1656045-Muscle Contraction, pubmed-meshheading:1656045-Phenylalanine, pubmed-meshheading:1656045-Rats, pubmed-meshheading:1656045-Receptors, Opioid, pubmed-meshheading:1656045-Receptors, Opioid, delta, pubmed-meshheading:1656045-Receptors, Opioid, mu, pubmed-meshheading:1656045-Stereoisomerism, pubmed-meshheading:1656045-Structure-Activity Relationship, pubmed-meshheading:1656045-Tetrahydroisoquinolines, pubmed-meshheading:1656045-Tetrahydronaphthalenes

Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue: effects on receptor selectivity and stereospecificity.

Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't