N-methylated cyclic Enkephalin analogues retain high opioid receptor binding affinity

Abstract

In an effort to improve the bioavailability of the non-selective, cyclic enkephalin analogues H-Dmt-c[d-Cys-Gly-Phe-d(or L)-Cys]NH2 (Dmt = 2',6'-dimethyltyrosine), analogues N-methylated at the Phe4 and/or Cys5 residue were synthesized. In comparison with the non-methylated parent peptides, all mono- and N-di-methylated analogues in general retained high binding affinities at all three opioid receptors and high opioid agonist potencies in functional opioid activity assays. The results indicate that the progressive conformational restriction in these compounds upon mono- and di-N-methylation did not significantly affect the in vitro opioid activity profile. A low-energy conformer identified for the conformationally most restricted analogue of the series, H-Dmt-c[D-Cys-Gly-Phe(NMe)-L-Cys(NMe)]NH 2 (6), showed good spatial overlap of the essential pharmacophoric moieties with those in the proposed μ receptor-bound conformation of the μ-selective opioid peptide JOM-6 [H-Tyr-c(S-Et-S)[D-Cys-Phe-D-Pen]NH 2] (Pen = penicillamine) [Mosberg M.I. and Fowler C.B. (2002) J Peptide Res; 60:329-335], in agreement with the moderate μ selectivity determined for this compound. An analogue of 6 containing (2S)-2-methyl-3-(2,6- dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in place of Dmt1 was an opioid antagonist with quite high opioid receptor binding affinities and can be expected to show improved bioavailability because of its further increased lipophilicity and reduced hydrogen-bonding capacity. © 2009 John Wiley & Sons A/S.