Leu-enkephalin analogs

Recently, the Leu-enkephalin analog containing a novel derivative of Dmt lacking a basic amine [(2(S )-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyDpropanoic acid, (2S)-Mdp, Fig. 7.431 was reported this peptide is an antagonist in both the MVD and GPI smooth muscle preparations, with fivefold higher potency in the MVD (739). 

On examination of the structures of the enkephalin and the structure-activity relationships published by late 1980, we were struck two observations. First, highly potent enkephalin analogs could be prepared by substituting Gly-2 by a large variety of D-amlno acids, and Met-5 (or Leu-5) could be replaced by a large variety of L- or D-amlno acid and lead to a potent enkephalin analog. Second, the Gly-2, Met-5 combination Is highly reminiscent of the Met-4, Gly-10 situation In o-MSH. 

Table II. Receptor Blading Affinities of Enkephalin Analogs for [ H]-Labelled Naloxone ([ HJNAL) and [ H)-Labelled CD Ala, D-Leu lEnkephalln (I HlDAPLE) In Rat Brain Homogenates ...

Scheme 5.1.5. Clostripain-mediated coupling of the Leu-enkephalin sequence Z-Asp-Tyr-Gly-Gly-Phe-Leu-OH with a moenomycin A analog.

The analogous enkephalin Tyr-D-Ala-Gly-Paa-Leu39) only exerts a slight opiatelike effect in comparison with Leu-enkephalin 17. The exchange of Phe4 for Paa (/J-pyrazinylalanine) leads to a severe loss of activity. 

Aminoindane and related ring systems have also been employed as conformational restraints of enkephalins. The analog 24 in which 1-aminoindane replaces residues 4 and 5 of the pentapeptide retains half the GPI activity of DADL,(45) while the peptide 25 modified at the Tyr residue exceeds Leu-enkephalin in potency seven to eight times, but is 30 times less effective at MVD sites.(183) The last derivative showed no activity in mice, using the... 

Photoaffinity labels have also been investigated. These are enkephalin analogs containing a photosensitive group [e.g., 4-azidophenyl or 2-nitro-4-azidophenyl (NAP)] that form a covalent bond upon irradiation with UV light. Thus, both the peptide 11<37) and the Leu-enkephalins 12(38) bind strongly to brain membranes on photolysis, and the latter pair have been shown to cause a 20-30% inactivation of opioid receptors. Further work on affinity labels and related topics is described in the 1982 and 1983 reports of the International Narcotics Research Conference/39 ... 

Simulated annealing has also been applied to the conformational study of dipeptide models of Gly, Ala, and Asp pentaglycine and Leu-enkephalin [11] an analog of vasopressin [10] (3S, 4S)-statin [12] analogs of thyrotropin releasing hormone [13] and the C-peptide of Ribonuclease A [13]. 

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