7-spiroindanyl derivatives of naltrexone and oxymorphone as selective ligands for delta opioid receptors

A series consisting of spiroindanyl (5-7), benzospiroindanyl (8-10), and spiroperinaphthyl (11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the role of an orthogonal-oriented ''address'' for delta opioid receptors. All of the ligands exhibited a preference for delta receptors in vitro. The 7-benzospiroindanyl derivative 8 (BSINTX) was the most selective delta opioid receptor antagonist in vitro. In mice BSINTX antagonized the delta(1)-selective agonist, [D-Pen(2),D-Pen(5)]enkephalin without significantly affecting the antinociceptive potency of delta(2), mu, and kappa agonists. The results of this study are consistent with an orthogonally-oriented address favoring delta(1) activity.