Structure-activity relationships, opioid ligands

Apart from a few notable exceptions (see later), all known narcotic antagonists are based on the morphine, morphinan, or benzomorphan polycyclic systems, that is, on three closely related groups of opioid ligands that share many structure-activity relationships (see Chapters 2, 3, and 4). Details of antagonist representatives of each group will now be given, chiefly confined to N- allyl and N-cyclopropylmethy 1 (CPM) derivatives, with minimal chemical details. 

OVERALL STRUCTURE-ACTIVITY RELATIONSHIPS OF OPIOID LIGANDS... 

Structure-Activity Relationships of Nonpeptide Opioid Ligands... 

A variety of affinity labels, mostly nonpeptide ligands, have been prepared for opioid receptors. Detailed reviews of the structure-activity relationships for affinity labels have been published [see the previous edition of this chapter (286) and Refs. 319, 594-5961. Therefore the discussion below focuses on those ligands that have been most useful in the characterization of opioid receptors, and oi recent reports of new affinity label derivatives. 

Yongye, A. B., Appel, J. R., Giulianotti, M., Dooley, C. T., Medina-Franco, J. L., Nefzi, A., Houghten, R., and Martinez-Mayorga, K. (2009). Identification, binding mode prediction and structure-activity relationships of potent triamine and piperazine opioid ligands. 

Alfaro-Lopez J, Okayama T, Hosohata K et al (1999) Exploring the structure-activity relationships of [l-(4-tert-butyl-3 -hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective 8-opioid receptor nonpeptide agonist ligand. J Med Chem... 

Numerous ligands have been developied as potential opioid receptor probes in an effort to distinguish between different types of opioid receptors. These include peptide [6,7] and nonpeptide [8] agonists and antagonists. Here we discuss the design and structure-activity relationship studies of 6-selective nonpeptide ligands and the role of conformation of the "address" moiety in conferring selectivity to the Si and 2 subtypes of opioid receptors. 

Due to their high selectivity, DER and DEL were the basis for an extensive structure activity relationship study aimed to understand the essential requisites of p. and 8 activity. More than 200 analogues of DER and DEL C were synthesized, and the role of each amino acid in binding to p and 8 receptors and bioactivity was defined [21-31]. New synthetic products were prepared such as oxymorphindole and related derivatives [32], and (+)-4-[(alfa R)-alfa-((2S,5R)-4-allyl-2.5-dimethyl-l-piperazin-yl)-3-methoxy-benzyl]-N, diethylbenzamide [33]. These products are under investigation for their clinical relevance and provide potential nonpeptide ligands for studies on delta-opioid-receptor. 

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