Synthesis of Selective Cyclic Opioids

Goodman, Murray

Abstract

In our laboratories, we employ an integrated approach for the development of highly active, selective, and metabolically stable opioid analogs. This approach encompasses design, syntheses, biological studies and conformational analyses and is supported through two separate but complementary NIH grants (NIH DA 05539 and NIH DA 06254). This application, outlining our synthetic efforts, will concentrate on two major areas; 1) the dermorphin-deltorphin family and 2) delta-receptor selective agonists and antagonists. For the dermorphin-deltorphin studies, we plan to synthesize sidechain- mainchain cyclized opioids and their novel (the retro-inverso modified and diacylhydrazine [C(O)-NH-NH-C(O)]) analogs. Since our previous application for this grant, we have synthesized Tyr-c[D-Orn-Phe-Xaa] (Xaa = Ala, Beta Ala and Abu [aminobutyric acid]) and bioassays of the compounds are underway. The preliminary results indicate that the compounds are highly active and their bioactivity profiles are in good agreement with our conformational model for opioid activity. We will synthesize seven modified analogs: Tyr-c[D-Orn-gPhe-X] (X=malonyl, succinyl and glutaryl residues), Tyr-c[D-Adp-gPhe-diaminoethylene](Adp: 2-aminoadipic acid) and Tyr-c[D-Adp-gPhe-r/Beta/Ala] as the retro-inverso modified analogs and for the hydrazino modification, Tyr-c[D-Glu-Phe-Gly- NH-NH] and Tyr-c[D-Lys-Phe-Azgly][Azgly: NH2-NH-C(O)-]. The target molecules were determined by preliminary conformational calculations (NIH DA 06254). To synthesize delta-selective agonists, we will incorporate the lanthionine (monosulfide) bridge. Lanthionine analogs of bioactive peptides are more potent, metabolically stable and constrained than their disulfide counterparts. In addition, the lanthionine modification does not change the conformational preferences of the disulfide counterpart. Local constraints, utilized to enhance delta-selectivity, will be introduced to yield Tyr-c[D-AlaL-Gly-Pre-Xaa]-OH[Xaa=(Beta/Me)AlaL and (Beta/Me, NMe)AlaL]. In addition, we plan to cyclize the N-terminal pentapeptide of the delta-selective deltorphin I: Tyr-c[D-AlaL-Phe- Asp/Ala-AlaL]-OH. The target compounds Tyr-cis&trans-Beta/Atnc-Phe-NH2 and Tyr-cis&trans- Beta/Atnc-Phe-Phe-NH2 (Beta/Atnc:3-amino-1,2,3,4-tetrahydronaphthalene-2- carboxylic acid) have been designed to probe delta-selective antagonism. These compounds arise from our Beta-amino acid containing morphiceptin analogs and Schiller's new antagonists TIP-NH2 (Tyr-Tic-Phe-NH2, Tic denotes 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) and TIPP-NH2 (Tyr-Tic-Phe-Phe-NH2). The compounds synthesized will be subjected to comprehensive biological studies and conformational analyses (NIH DA 06254). The results from these studies will be utilized to enhance our understanding of the conformation-bioactivity relationships of opioid agonists and antagonists. These ongoing efforts will lead to the design of additional modifications and provide pharmacologically useful compounds.