7-Arylidenenaltrexones as selective δ₁ opioid receptor antagonists

A series of 7-arylidinenaltrexones (2a-m) related to the prototypical δ₁-selective antagonist, 7-benzylidenenaltrexone 1 (BNTX), have been synthesized in an effort to develop more selective ligands. Testing in smooth muscle preparations revealed that members of the series exhibited varying degrees of selectively for δ receptors, with the o-methoxy (2e) and o- chloro (2j) congeners being most potent and most selective (Ke ~ 0.8 nm). Evaluation of 1, 2e, and 2f sc in mice using the tail-flick procedure indicated that they are selective δ₁ opioid receptor antagonists in the lower dose range. At high doses these ligands, including BNTX, exhibited decreased δ₁ selectivity due to increases in the ED₅₀ ratios of [D- Ser²,Leu⁵]enkephalin-Thr⁶ and morphine. It is concluded that 2e and 2f possess in vivo selectivity similar to that of BNTX, but are less potent as δ₁ antagonists.