The long-term objectives of the proposal are to synthesize and develop highly selective delta1- and delta2-selective opiate antagonists. These agents will have implications in determining the potential role of delta- opiate receptors in pathophysiological states as well as in the treatment of certain disorders. The compounds to be studied will be designed with variation around the C-6, C-7 positions of the mophinan system. A comparison of key interatomic distances of known delta-selective opiate antagonists suggests that a set of three distances are important in determining selectivity. Structure activity relationships also suggest that the presence of an aromatic moiety in the C-6, C-7 region is important. To test this hypothesis, the structures of naltrexone and naloxone will be modified by having some heteroaromatic systems, such as various azoles fused to them, specifically at C-6 and C-7. It is planned to synthesize a number of 3,14Beta-dihydroxy-4,5alpha-epoxy-6,7- didehydro-17-(cyclopropylmethyl-orallyl-)morphinians to which are attached at C6 and C-7:(2'-alkyl-or2'-aryl)-4',5'-imidazoles,(2-alkyl- or2'-aryl)-4',5'-thiazoles, and 8',7'-imidazol[1,2- a]pyridines(substituted in the pyridine ring). In addition, a number of 7-(heteroarylidene)-and 7-(alpha- and Beta-heteroarylmethyl)-naltrexones and nalozones will be prepared, where the heteroaryl groups initially will be 2-furyl, 2-pyrryl, 3-indolyl, 2-,3-, and 4-pyridyl. The components will be included for their activity at mu, delta1, delta2 and k-opiate receptors by determining the IC50 and k(i) values for their displacement of highly selective 3H-ligands, 3H-DAMGO (mu), 3H-U-69593 (k), 3H-DPDPE (delta1) and 3H-DSTLE (delta2) in presence of 100 nM DAMGO to suppress mu sites.) The selectivity will be considered high if the ratio of k(i) at any ligand to the k(i) at delta site is high. Mouse vas deferens (MVD) and guinea-pig ileum (GPI) preparations will also be used to assess the selectivity of the synthesized compounds. IC50 values for various agonists (mu, delta, K) will be determined in the presence and absence of a known concentration of the test compound. This will be followed by the determination of the IC50 ratios, k(e) values and their ratios (mu/delta and k/delta) and the analysis and interpretation will be made as above. Finally, in vivo activity (analgesic) will be determined for mu, delta, and k agonists in the absence and presence of the test compound. The effects of intracerebroventricular and peripheral (subcutaneously) administration of the test compound for its ability to antagonize the activity of mu., delta, k - agonists in order to assess the hydrophobic nature of the compound (whether it can cross the blood- brain barrier) will be determined. These studies may lead to the development of highly selective delta-antagonists for in vitro and in vivo activity.
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