7-spirobenzocyclohexyl derivatives of naltrexone, oxymorphone, and hydromorphone as selective opioid receptor ligands.

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Fang X, Larson DL, Portoghese PS

7-spirobenzocyclohexyl derivatives of naltrexone, oxymorphone, and hydromorphone as selective opioid receptor ligands.

J Med Chem. 1997 Sep 12;40(19):3064-70.

PubMed ID

9301669 [ View in PubMed

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Abstract

On the basis of previous structure-activity studies of the highly potent and selective delta-opioid receptor antagonist naltrindole (1) and the spiroindanyl analogues 2 and 3, we have synthesized epimeric pairs of spirobenzocyclohexyl derivatives of naltrexone, oxymorphone, and hydromorphone (4-9). Pharmacologic evaluation in smooth muscle assays has revealed that the oxymorphone derivatives (6, 7) are delta-selective agonists and possess receptor binding profiles that are consistent with their agonist activity. It is proposed that the spirobenzocyclohexyl group of 6 and 7 orients its benzene moiety orthogonally with respect to the C ring of the opiate in a manner similar to that of the spiroindanyl analogue 3. It is suggested that this orthogonal orientation serves as an "address" to facilitate activation of delta receptors. The finding that the hydromorphone analogues (8, 9) were full mu agonists and exhibited only partial delta agonist activity suggests that the 14-hydroxyl group also contributes to the delta agonist activity. The naltrexone derivatives (4, 5) were mu-selective antagonists and exhibited relatively weak delta antagonist activity. However, the binding data indicated a very high-affinity delta-selective binding profile that was not consistent with the pharmacology. This study illustrates the differential contributions of the delta "address" to agonist and antagonist activity and supports the idea of different recognition sites for interaction of agonist and antagonist ligands with delta-opioid receptors.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Hydromorphone	Delta-type opioid receptor	Protein	Humans	Yes	Partial agonist	Details