Opioid antagonists structure-activity relationships

The primary purpose of this chapter is to review the structure-activity relationships (SAR) of non-peptide kappa opioid agonists and antagonists from the viewpoint of a medicinal chemist. It is intended to present an account of work in this area published in journals and in patents from 1985 up to the end of 1990. During the late 1980 s there was a significant increase in the literature on kappa opioids and this has resulted in several publications which, at the time of writing, have not been previously reviewed. Three pharmaceutical companies, Upjohn, Parke-Davis and Zambeletti (SB-Italy), have progressed kappa agonists into clinical trials, so it seems an appropriate and opportune time to review the preclinical data. 

Yoshikawa, M., Tani, F., and Chiba, H. 1988. Structure activity relationship of opioid antagonist peptides derived from milk proteins. In Peptide Chemistry (T. Shiba, ed.), pp. 473-476. Protein Research Foundation, Osaka. 

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. 

TRK-851 is a clinical candidate for an antitussive drug it has a novel, complex morphinan ring system. The development of TRK-851 was motivated by the finding that NTI, a selective 8 opioid receptor antagonist, showed antitussive effect. In this section we will describe the process of developing TRK-851, including the structure-activity relationship (SAR) studies on NTI derivatives and the difficulties encountered in overcoming a defect in the metabolism of a prototype clinical candidate, TRK-850. 

Fiirst S, Hosztafi S, Friedmann T (1995) Structure-activity relationships of synthetic and semisynthetic opioid agonists and antagonists. Curr Med Chem 1 423-440... 

This review focuses on the advances on the structure-activity relationship (SAR) studies on the diarylmethylpiperazine derivatives of the SNC 80 type, with agonist or antagonist properties at the 5 opioid receptors, as well as provides a description of the synthetic procedures used in the synthesis of SNC 80 and its analogs. 

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. 

Structure activity relationships of synthetic and semisynthetic opioid agonists and antagonists... 

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