Opioid peptides conformational studies

The spin-spin coupling constants [2-4] of the enkephalins in solution can be interpreted in terms of folded conformations resembling that of morphine in the placement of the residues which appear important for biological activity. X-ray crystallography and theoretical calculations (4-9) have also shown that methionine and leucine enkephalin adopt conformations similar to those concluded from NMR studies. Hence it would appear that opioid peptides can topographically resemble the opiates by assuming preferred, folded, conformations. However, earlier studies from this laboratory (TO) have shown that NMR data can be interpreted in terms of a conformationally flexible structure for methionine enkephalin. 

Quantum mechanical calculations have been applied to opioid peptides in attempts to identify low-energy conformers and to study their relationships to rigid opioids. Of the 52 conformations reported for met-enkephalin,(205) the lowest-energy structures (those with AE = 2.5 kcal/mol) were found to have... 

R 64 J. Malicka, C. Czaplewski, M. Groth, W. Wiczk, S. Oldziej, L. Lan-kiewicz, J. Ciarkowski and A. Li wo, Use of NMR and Fluorescence Spectroscopy as well as Theoretical Conformational Analysis in Conformation-Activity Studies of Cyclic Enkephalin Analogues , p. 123 R 65 A. Naito and K. Nishimura, Conformational Analysis of Opioid Peptides in the Solid State and the Membrane Environments by NMR Spectroscopy , p. 135... 

Numerous ligands have been developied as potential opioid receptor probes in an effort to distinguish between different types of opioid receptors. These include peptide [6,7] and nonpeptide [8] agonists and antagonists. Here we discuss the design and structure-activity relationship studies of 6-selective nonpeptide ligands and the role of conformation of the "address" moiety in conferring selectivity to the Si and 2 subtypes of opioid receptors. 

The bioactive conformation is consistent with the farmacoforic points that are identified through structure activity relationship studies (SAR). SAR studies include the synthesis of many peptide and/or non peptide analogues displaying selectivity for one or another of the receptors and their pharmacologically defined subtypes [19] such as delta 1- and delta2-opioid receprtor subtypes [20]. 

In some cases, redundant amino acids may render analysis more complex. In the case of the opioid pentapeptide enkephalin, Tyr-Gly-Gly-Phe-Met, analysis has been aided by the incorporation of stereochemically deuterated glycine residues. Such studies have shown that conformational averaging in the peptide backbone must occur in order to account for the observed spin-spin couplings (Fishman et a/., 1978). 

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