Minimum-structure enkephalin analogues incorporating L-tyrosine, D(or L)-phenylalanine, and a diamine spacer.
In order to test the theory that high mu-activity of opioid peptides could be elicited by the presence of an amino-terminal L-Tyr residue and a Phe aromatic ring held in the proper relative spatial disposition, a novel series of hybrid retro peptides were prepared in which L-Tyr was linked to N-acyl Phe through a variety of diamine spacers. These compounds were evaluated for opioid agonist and antagonist activity in the guinea pig ileum (GPI) in vitro assay. Analogues containing a 1,2-ethanediamine spacer, which conferred a Tyr-Phe separation distance closest to that found in Phe3 opioid peptides, were more potent agonists than the corresponding analogues containing a 1,3-propanediamine spacer. Agonist activity was observed for both L-Phe and D-Phe analogues, consistent with the known activity for both Phe stereochemistries for certain Phe3 opioid peptide analogues. Concerning the diamine spacer, conformational constraints imposed by 4-aminopiperidine and 4-(aminomethyl)piperidine as well as the presence of a hydroxyl group eliminated activity, but the presence of gem-dimethyl substitution next to the nitrogen attached to Tyr increased activity substantially for the D-Phe derivatives. Removal of the N-acetyl group from Phe did not eliminate activity. Naloxone Ke values determined for six of the most potent analogues are indicative of predominantly mu-agonism, but the D-Phe compounds 3a and 6a (1.4-2.1 nM) appear to be more mu-selective than the L-Phe compounds 2b, 3b, 5b, and 6b (3.3-4.4 nM), even though the latter are more potent agonists. Compounds 3a and 3b, which were found to be 10 and 21 times more potent, respectively, than morphine in the GPI, are two of the most structurally simple yet potent opioid peptide analogues described to date.
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
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Jacobson
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Gintzler
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Sayre
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003959:Diamines; D004745:Enkephalins / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010649:Phenylalanine; D013329:Structure-Activity Relationship; D014443:Tyrosine
D003959:Diamines; D004745:Enkephalins; D014443:Tyrosine; D010649:Phenylalanine