The interaction of a diverse set of opioid alkaloids and peptides with various
opioid receptors has been examined using biochemical and pharmacological
techniques. Structural information on the compounds was obtained from
single crystal X-ray diffraction and nuclear magnetic resonance studies, and
modelled by computational methods.
The introduction of a dithiocarbazate moiety into the 7a-position of a bridged
thebaine was shown to afford a degree of μ selectivity in this class of nonselective
compounds. X-ray diffraction analysis of this compound and
comparison with the structure of [Met5]enkephalin showed the importance of
the sulphydryl moiety. The conformation of [Leu5]enkephalin, in which the
amino acid methionine is replaced by leucine, at the same receptor is unlikely
to be similar. A series of morphinan derivatives which had been developed as
μ-antagonists were evaluated. Substitution patterns of the morphinan ring
nucleus and their effect upon activity were examined. X-ray analysis of several
key compounds was performed. Unexpectedly a 3-hydroxymorphinan-6-one
analogue showed an ability to differentiate apparently similar opioid Kreceptors.
The implications in terms of K-receptor subtypes are discussed. The opioid receptor binding characteristics of structurally diverse K-receptor
ligands were examined in two different buffer systems. Electrostatic modelling
of the K-ligands, based upon crystal structure coordinates, was performed.
From electrostatic potential maps a requirement for ligands acting at Kreceptors
is postulated. Solution conformations of the endogenous K-ligand,
dynorphin A(1-8), were determined by nuclear magnetic resonance studies and
compared with the wo preferring [Leu5]enkephalin. Models were proposed
based upon dihedral angles determined from HCtl-NH coupling constants,
amide proton-deuteron exchange and amide proton temperature coefficient
data. Candidate conformations were shown to be stable under dynamic
simulation conditions. Electrostatic modelling of a chosen dynorphin An-8)
conformation gave results comparable with the observed electrostatic model of
the K-ligands. The proposed model is discussed in terms of its suitability as a
retro-model for the active site ofthe K-opioid receptor.
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.