X-ray diffraction studies of enkephalins and opiates.

Information on intramolecular geometry, low energy conformations, hydrogen bonds, both intramolecular and intermolecular, and preferred intermolecular interactions is obtained from single crystal X-ray diffraction experiments. Structure determinations of crystals with more than one molecule in the asymmetric unit and of different crystalline forms provide information on conformational flexibility and stable aggregation states. The single crystal X-ray diffraction studies of enkephalin have demonstrated a number of minimum energy conformations of the main chain and side chains, a type I' beta turn centered on Gly2Gly3 and a number of extended main-chain conformations. In the studies of native enkephalins, dimers and tetramers form repeating units, and some patterns of solvation are observed in more than one form. Certain conformations and interactions proposed on the basis of solution spectroscopic studies have yet to be observed in the solid state. Efforts should be made to grow different crystalline forms of the enkephalins and to determine the solid state structure of enkephalin analogues that exhibit high selectivity for a particular opioid receptor subtype. Crystallographic studies of opiate drugs with selective activity profiles at different receptor subtypes can give information on the features responsible for active site differentiation between the subtypes of opioid receptor. Analysis of the crystallographic data base of 30 compounds containing the five fused-ring morphine moiety indicate that: (1) the methyl group on the piperidyl nitrogen prefers the equatorial position, (2) the conformation of the piperidyl ring is a relatively invariant chair conformation, (3) C-ring conformation depends on the chemical constitution of the C-ring and substitution at C6.