An approach to the design of receptor-type-selective non-peptide antagonists of peptidergic receptors: delta opioid antagonists.
Approaches to the design of peptidomimetic ligands are currently of great interest because of the discovery of an increasing number of endogenous peptides that modulate physiological processes. The inherent lability of peptides and their poor oral absorption have made peptidomimetics attractive targets for drug development. In this presentation I have discussed the design of a novel series of delta-selective opioid antagonists based on the message-address concept. The opioid peptides can be viewed to contain two elements: an essential message component that is recognized by the receptor subsite responsible for the signal transduction process and an address element that is recognized by a subsite that is unique to a single receptor type and functions to enhance binding to the site. Since the tyramine moiety in opiate structures is known to be important for activity, an identical element in Tyr1 of the opioid peptides can be viewed as the message. A key moiety of the delta address was considered to be the phenyl group of Phe4. Combining the universal opioid antagonist naltrexone (5) with a strategically located address mimic afforded naltrindole (6, NTI), the first nonpeptide delta opioid receptor antagonist.
Portoghese
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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
D000595:Amino Acid Sequence; D015195:Drug Design; D004745:Enkephalins / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008969:Molecular Sequence Data; D009019:Morphinans / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives*; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta; D013329:Structure-Activity Relationship
D004745:Enkephalins; D007211:Indoles; D009019:Morphinans; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D009271:Naltrexone; C055382:naltrindole