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


, : Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue: effects on receptor selectivity and stereospecificity. Journal of Medicinal Chemistry 34(10): 3125-3132

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.

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PMID: 1656045


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