The thiophene 2 and pyran 3 analogues of the κ-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 κ opioid receptor antagonists in smooth muscle preparations, and they bound selectively to κ-recognition sites. The thiophene analogue 2 displayed binding selectivity that was of the same order of magnitude as that of la, while 3 was considerably less selective for κ site. This is consistent with the fact that the second pharmacophore in la and 2 displayed a greater degree of superposition than la 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 κ opioid receptor.