binaltorphimine and norbinaltorphimine

The thiophene 2 and pyran 3 analogues of the kappa-selective opioid antagonist norbinaltorphimine (1a, norBNI) were synthesized and tested in an effort to determine the contribution of the spacer to the interaction of bivalent ligands at different opioid receptor types. Both 2 and 3 were found to be selective kappa opioid receptor antagonists in smooth muscle preparations, and they bound selectively to kappa-recognition sites. The thiophene analogue 2 displayed binding selectivity that was of the same order of magnitude as that of 1a, while 3 was considerably less selective for kappa site. This is consistent with the fact that the second pharmacophore in 1a and 2 displayed a greater degree of superposition than 1a and 3. The results of this study suggest that the pyrrole moiety of norBNI functions primarily as an inert spacer to rigidly hold the basic nitrogen in the second pharmacophore at an "address" subsite that is unique for the kappa opioid receptor.

Topics: Animals; Binding, Competitive; In Vitro Techniques; Indicators and Reagents; Kinetics; Ligands; Male; Molecular Conformation; Molecular Structure; Muscle Contraction; Muscle, Smooth; Naltrexone; Receptors, Opioid; Receptors, Opioid, kappa; Structure-Activity Relationship

The opioid antagonist activities of two bivalent ligands, BNI and nor-BNI, have been evaluated in smooth muscle preparations and in mice. Both ligands are highly potent and selective as kappa opioid receptor antagonists, with relatively feeble blocking activity at mu and delta opioid receptors. BNI and nor-BNI represent the first highly selective kappa opioid receptor antagonists and should be of great utility as molecular probes for identifying the interaction of agonist ligands with kappa opioid receptors in vitro and in vivo.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Chemical Phenomena; Chemistry; Cyclazocine; Dynorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Ethylketocyclazocine; Guinea Pigs; Male; Mice; Morphine; Naloxone; Naltrexone; Pyrrolidines; Rabbits; Receptors, Opioid; Receptors, Opioid, kappa