Kappa selective ligands

ATTEMPTS TO DEVELOP KAPPA-SELECTIVE LIGANDS FROM OTHER CHEMICAL LEADS... 

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. 

This concept was tested by attaching a peptide address to an opiate pharmacophore [4]. When the address segment of leucine-enkephalin (delta-selective) or dynorphin A (kappa-selective) was linked to oxymorphone through a spacer, a change in selectivity was observed. The mu-selective opiate, oxymorphone, was transformed to a delta-selective ligand by the attachment of the delta address (Phe-Leu) of leucine-enkephalin. Similarly, a kappa-selective ligand was obtained upon attachment of the kappa address (Phe-Leu-Arg-Arg-TLe-OMe) of dynorphin A (Fig. 2). 

The peptide (3 -iodo Tyr1 )-D-Pro10-dynorphin A [1-11] had a potent K value of 0.21 nM (Table 3), which was similar to the Kd of its radioactive analog (0.16 nM). Of the kappa-selective ligands, U-50,488 and U-69,593 were... 

TABLE 3 Activity of Kappa-Selective Ligands in Opioid Receptor Binding Assays and Kappa GTPy[35S] Assay... 

Nishi M., Takeshima H., Fukada K., Kato S., Mori K. cDNA cloning and pharmacological characterization of an opioid receptor with high affinities for kappa-subtype selective ligands. FEBS Lett. 330 77, 1993. 

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

OTHER REVIEWS OF THE OPIOID LITERATURE INTRODUCTION SELECTIVE KAPPA OPIOID LIGANDS KAPPA RECEPTOR SUBTYPES... 

Dooley, C.T., Ny, P., Bidlack, J.M. and Houghten, R.A. Selective ligands for the sigma, delta, and kappa opioid receptors identified from a single mixture based tetrapeptide positional scanning combinatorial library./. Biol. Chem., 1998,273, 18848-1 8856. 

Delta and Kappa Opioid Receptors and Selective Ligands, 451... 

OH, 30) (111), and TIPPm (Tyr-Tic [CHgNHlPhe-PheOH, 31) (112), and the nonpeptide naltrindole (32) (113). Recently, however, TIPP has been reported to exhibit agonist activity in adenylyl cyclase assays (114). Early studies of k receptors used benzo-morphans such as ethylketocyclazocine (EKC, 33), a close analog of ketocyclazocine, and bremazocine(34) (Fig. 7.6), but the selectivity of these ligands for k receptors is very low (see Table 7.8 below). Kappa-selective agonists such as U50,488 (35) (115), U69,593 (36) (116), and CI-977 (37) (117, 118), and the... 

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