Enkephalins structure-activity relationships

The recent discovery of a class of peptides, the enkephalins, which act as opiate agonists has led to a number of physical chemical studies aimed at understanding the structure-activity relationships between the enkephalins and the opiates (1 -9). 

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. 

An examination of the structure-activity relationship (SAR) of a series of enkephalin analogues and morphine derivatives in competing with the binding of radioisotope labeled DADLE and FK 33-824 or opiates revealed that DADLE binds to an opioid receptor selective to Leu-enkephalin and its analogues. In contrast, FK 33-824, morphine, or naloxone binds to opioid receptors with selectivity in favor of morphine and derivatives simi-... 

Further information about the structure-activity relationships was obtained by Schiller et al.40) with retroinverso modifications of linear enkephalins, e.g. Tyr-D-Ala-gGly-mPhe-Leu-NH2 19 (14% Leu-enkephalin activity). 

Very soon after it became known that small peptides were capable of interacting with opioid receptors the investigation of analogs of the natural enkephalins commenced on an ever-increasing scale, and today literally hundreds of such derivatives have been tested for opioid properties. Before embarking on an account of the structure-activity relationships that have emerged, a short account of synthetic methods used in this field will be given. 

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