Kappa structure

Chi indices for the various isomers of hexane. (Figure adapted in part from Hall L H and L B Kier 1991. The ir Connectivity Chi Indexes and Kappa Shape Indexes in Structure-property Modeling. In Lipkowitz K B and id (Editors) Reviews in Computational Chemistiy Volume 2. New York, VCH Publishers, pp. 367-422.)... 

LH Hall, LB Kier. The molecular connectivity chi indexes and kappa shape indexes in structure-property modeling. In KB Lipkowitz, DB Boyd, eds. Reviews in Computational Chemistry, Vol. 2. New York VCH, 1991, pp 367-422. 

Consistent with their chemical differences, the molecular structures of i- and K-carrageenans are not identical. A shorter pitch and an offset positioning of the two chains in the kappa helix is compatible with the lack of sulfate group on every 3,6-anhydrogalactose residue. The variations in molecular structures mirror the types of junction zones formed by these polymers and relate to the observed gelation properties. 

Lowell H. Hall and Lemont B. Kier, The Molecular Connectivity Chi Indexes and Kappa Shape Indexes in Structure-Property Modeling. 

Chemical Structures and Biological Activities of Non-Peptide Selective Kappa Opioid Ligands... 

STRUCTURE-ACTIVITY RELATIONSHIPS OF SELECTIVE KAPPA AGONISTS BASED ON THE 1,2-AMINOAMIDE U-50488... 

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. 

A comprehensive review of receptor selective opioid peptide analogues by Schiller [7] appeared in the previous volume of this Series and for this reason the present chapter describes only non-peptide structures. A leading review which introduces kappa opioid analgesics was written by Horwell in 1988 [8] and a subsequent article focusing on kappa receptors and analgesia by Millan appeared in 1990 [9]. 

The 1,2-aminoamides are now established as a chemical series with several highly selective kappa opioid receptor agonists. However, the biological activity of 1,2-aminoamides is not restricted to kappa analgesics. Several related structures exhibit biological activity in other systems of importance and interest. In order to appraise the significance of this chemical class and to put the SAR for kappa receptor activity into context, a selection of these compounds is discussed here. This is not a comprehensive literature review but rather a selection of a few compounds to illustrate the broad range of medieinal activity exhibited by these somewhat similar chemical structures. 

The majority of studies aimed at preparing kappa-selective opioids have used U-50488 (5) as the chemical lead and, as the above discussion shows, this has proved to be a highly productive approach. However, as was pointed out above, there are other structures [EKC (3), tifluadom (6) and the peptide dynorphin (7)] which have been reported to bind to the kappa receptor, albeit with poor opioid receptor subtype selectivity. Some attempts have been made to develop kappa-selective ligands from these structures and they are summarized here. 

The structures of agarose, iota- and kappa-carrageenan have been determined by x-ray fiber diffraction (24-27). The quality of the diffraction data obtained from each of these three specimens varies considerably and the way in which these data are used in structure determination is outlined here. Diffraction patterns from oriented specimens of agarose, and kappa- and iota-carrageenan are shown in Figure 6 (28). The molecular repeat distances derived from these patterns are listed in Table I. 

Figure 7. Mutually perpendicular views of the (a) agarose, (b) iota-carrageenan, and (c) kappa-carrageenan double-helix structures. The two chains are shown with open and full bonds, and the 06—02 hydrogen bonds by broken lines. (Reproduced with permission from ref. 28. Copyright 1989 Elsevier.)...

Hall, L. H. and Kier, L. B. (1991) The molecular connectivity chi indices and kappa shape indices in structure-property modeling. In Reviews of computational chemistry, Boyd, D. B. and Lipkowitz, K. (eds.), Vol. 2. 

There are various opioid receptors the three major classes of opioid receptors are mu (p), delta (5) and kappa (k) receptors. The p, receptor is the principal pain-modulating site in the CNS, mediating the action of morphine. There is considerable interest in the K receptor, which mediates a sedating analgesia with decreased addiction liability and respiratory depression and which allows for some structural flexibility. Unfortunately, the K receptor seems to be coupled to the sigma (a) receptor, which is implicated in psychotomimetic and dysphoric side effects. 

Borgstrom, J., Piculell, L., Viebke, C., Talmon, Y. (1996). On the structure of aggregated kappa-carrageenan helices a study by cryo-TEM, optical rotation and viscometry. International Journal of Biological Macromolecules, 18, 223-229. 

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