NONPEPTIDIC AND PEPTIDOMIMETIC SELECTIVE DELTA LIGANDS

This Project application is a broad collarative effort on the part of
seven investigator in four institutions to study the hypothesis that
opioid delta (delta) receptor subtype-selective agonist, partial agonist
and antagonists may be feasible candidates for development as therapeutic
agents related to the treatment of pain and addiction. These
investigator bring expertise ranging from extensive experience in
synthetic chemistry and molecular modeling, in pharmacological analysis
of molecules in vitro and in vivo, in application of molecular
techniques, to evaluation of behavior in several species including
primates. Emphasis in this effort will be two-fold. First, the
investigator will attempt to discover, and evaluate in several species,
highly receptor subtype-selective delta ligands through a
synthetic/pharmacological collaboration in order to test the underlying
hypothesis. Second, the novel ligands, and other available
pharmacological tools, will be employed to explore in greater detail the
pharmacology and physiology of subtypes of opioid delta receptors.
Strong collaborative interaction already exists and will be emphasized.
The specific aims are to: (a) synthesize novel, non-peptidic opioid delta
subtype-selective ligands using state-of-the-art synthetic, analytical
and modeling technology with emphasis on development of a structure-
activity relationship for delta subtypes, creation of affinity ligands
for characterization and localization of the receptors, and radio ligands
for PET and SPECT applications; (b) to synthesize sufficient quantities
of these compounds for the biological projects; (c) to evaluate the novel
non-peptidic molecules for their receptors selectively in vitro and to
characterize them in the Biological Evaluation Core; (d) to evaluate the
pharmacology of selective novel non-peptidic agonist using approaches in
vivo in antinociceptive, gastrointestinal and behavioral endpoints in
mice, rats, pigeons and monkeys; (e) to determine the affinity and
activity of the new compounds at the cloned opioid delta receptor(s)
following transfection of the receptors to cell lines, with particular
emphasis on the human delta receptor(s); (f) to determine the second
messenger systems involved in the mechanisms of action of compounds
acting selectively at delta receptor subtypes in the naive and opioid-
exposed tissue; (g) to evaluate the pharmacology of the selective novel
non-peptidic antagonists following repeated exposure alone or in
combination with opioids or cocaine using place pairing and self-
administration paradigms; (h) to perform detailed pharmacological studied
of the possible development of physical dependence via the delta
receptor; and (i) to collaborate with outside consultants to obtained any
data necessary to assess the central hypothesis of potential clinical
importance of opioid delta ligands. It is expected that this
multidisciplinary effort will result (a) in a realistic assessment of the
therapeutic potential of opioid delta receptors subtype-selective
ligands, (b) in the discovery of molecules with potential for development
as therapeutically useful substances, and (c) in the advancement of our
understanding of the role of opioid delta receptors and their subtypes
in normal and pathological physiology.