DALARGIN AND [CYS-(O2NH2)](2) ANALOGS OF ENKEPHALINS AND THEIR SELECTIVITY FOR MU-OPIOID RECEPTORS

1. Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newl y synthesized analogues-[Cys-(O2NH2)](2)-Met-enk (CM) and [Cys-(O2NH2) ](2)-Leu-enk (CL)- and of a hexapeptide-D-Ala(2)Leu(5)-Arg(6) (Dalargi n; DL) on the spontaneous and electrically stimulated activity were ex amined with respect to their selectivity for the mu opioid receptors i n the longitudinal layer of guinea pig ileum. 2. M and CM exerted rela xing and contractile effects on the spontaneous contractile activity w hile L, CL and DL produced only relaxation. The order of potency towar ds the relaxatory phase was DL > M > CM > L > CL and towards the contr actile phase CM > M. 3. The effects of enkephalins on the spontaneous activity were naloxone and TTX sensitive except for the contractile ph ase of M and CM which persisted in the presence of TTX. NO was not inv olved in the neurotransmission of the relaxatory responses, while the blockade of alpha and beta adrenoceptors showed the participation of a drenergic mechanisms. Relaxation and contraction induced by enkephalin s could not be directly attributed to cholinergic neurotransmission. 4 . The naloxone-sensitive and concentration-dependent inhibitory effect s of enkephalins and their analogues on the electrically stimulated ch olinergic contractions were established. The order of the relative pot ency of opioids was: DL-3.8; M-1.0; L-0.4; CM-0.01; CL-0.005. 5. These data indicated that the D-Ala(2) substitution and lengthening of the peptide chain by Arg(6) in the molecule of L increased the potency at the mu opiate receptors, while the substitution in position 2 with Cys -(O2NH2) in the molecule of M and L yielded a less potent and selectiv e mu agonists.