SYNTHESIS OF NALTREXONE-DERIVED DELTA-OPIOID ANTAGONISTS - ROLE OF CONFORMATION OF THE DELTA-ADDRESS MOIETY

Naltrindole (1) (NTI) is a highly potent and selective delta-opioid re ceptor antagonist. In an effort to understand the origin of the high p otency, affinity, and selectivity of NTI, we have examined the conform ational role of its indolic benzene moiety through the synthesis of re lated naltrexone derivatives 3-8, which contain the benzene moiety in different orientations and at different attachments in the molecule. O ne of these naltrexone derivatives, 5, whose 7-indanyl benzene moiety is orthogonal to ring C of the morphinan system, is a potent F-opioid receptor antagonist in vitro and in vivo. Computer-assisted molecular overlay studies of the minimized structures (2-8) revealed the importa nce of the position of the benzene moiety for effective interaction wi th delta-opioid receptors. In compounds 2, 4, and 5, the aromatic ring falls in the same region of space as that of the indolic benzene moie ty of NTI, and all of these ligands possessed significant activity at delta-opioid receptors. Analogues (3 and 6-8) which were shown to have relatively weak delta-opioid receptor antagonist potency have their a romatic groups located in a space that is different from that of the m ore potent analogues.