Kappa selective

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

It has been proposed, on the basis of observations made using the benzo-morphan derivative (MR 2034) (8), that all kappa agonists may cause undesired dysophoria and even psychotomimesis in man [27]. Benzomorphans such as MR 2034 with affinity for sigma receptors are well-known to be associated with dysphoria. To date, there has been no report of a dose-ranging clinical study with a truly kappa selective agonist which describes the analgesic effects and the onset of dysphoric symptoms. 

As discussed above, the discovery by the Upjohn Company in 1982 of U-50488 (5) was a milestone achievement in opioid research. This compound has significantly greater selectivity for the kappa opioid receptor than the previously used ketazocine (2) or EKC (3) and its widespread use in opioid research to study the properties of the kappa receptor has led to its being generally regarded as the prototype non-peptide kappa selective agonist. 

Table 3.4. OPIOID RECEPTOR BINDING SELECTIVITY OF ZT-52656A (42) COMPARED WITH OTHER KAPPA-SELECTIVE AGONISTS [63]...

The Sankyo company have shown that conformational restriction of the arylacetamide fragment of the Zambeletti/Glaxo series as in the indane derivative (49) preserves kappa selectivity (kappa A) = 0.67 nM, mu K, = 698 nM, mouse phenylquinone-induced writhing ED50 = 1.3 mg/kg s.c.) [72]. This aromatic group contains two of the rings found in the acenaphthene derivatives (26, 27) described above. 

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... 

Gerak LR, Butelman ER, Woods JH, France CP (1994) Antinociceptive and respiratory effects of nalbuphine in rhesus monkeys. J Pharmacol Exp Ther 271 993-999 Howell LL, Bergman J, Morse WH (1988) Effects of levor-phanol and several kappa-selective opioids on respiration and behavior in rhesus monkeys. J Pharmacol Exp Ther 245 364-372... 

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... 

Some kappa selective compounds have recently been progressed into clinical trials, although to date results describing their analgesic properties in humans have not been published. Potential side-effects include diuresis, sedation and possibly dysphoria. 

O 13 X more potent analgesic than U-50488 o (-) enantiomer more potent and more selective O des chloro derivative is highly kappa selective (U-69593)... 

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