Agonists kappa

All clinically used opiates have the same pharmacology since they all act on the mu receptor with the exception of the kappa agonist, pentazocine. Opiates are used to relieve moderate to severe pain whatever the cause (accidents, post-operative pain, cancer, etc.) and are used pre-, intra- and post-operatively. The mu opiates differ only in potency and pharmacokinetics. Examples are ... 

Walsh S.L., Geter-Douglas B., Strain E.C., Bigelow G.E. Enadoline and butorphanol evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans. J. Pharmacol. Exp. Ther. 299 147, 2001. 

Sawynok J. (1995). Pharmacological rationale for the clinical use of caffeine. Drugs. 49(1) 37-50. Sawynok J. (1998). Adenosine receptor activation and nociception. Eur J Pharmacol. 347(1) 1-11. Schlaepfer TE, Strain EC, Greenberg BD, Preston KL, Lancaster E, Bigelow GE, Barta PE, Pearlson GD. (1998). Site of opioid action in the human brain mu and kappa agonists subjective and cerebral blood flow effects. Am J Psychiatry. 155(4) 470-73. 

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. 

It is of historical interest to note that the disclosure of U-50488 occurred at roughly the same time as two chemically unrelated compounds which behave as poorly selective kappa agonist analgesics. These are the benzodiazepine, tifluadom (6) [17] and the amino-terminal nonapeptide fragment of dynorphin, Dyn (1-9), (7) (kappa A) = 0.21 nM, mu K = 3.6 nM delta K, = 3.2 nM) [18], which is thought to be the endogenous kappa opioid agonist. 

The biochemical and pharmacological properties of the kappa receptor and the differences between the kappa, mu and delta receptors have been reviewed elsewhere. The reader is directed to the opioid review articles by Rees and Hunter (1990) [4], Casy (1989) [3] and Leslie (1987) [10] and also to two shorter reviews which deal specifically with kappa agonists the review by Horwell published in 1988 entitled Kappa Opioid Analgesics [8] and the review by Millan in 1990 on kappa opioid receptors and analgesia [9]. An account of the medicinal chemistry of selective opioid agonists and antagonists was published in 1990 by Zimmerman and Leander [5]. 

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. 

In electrophysiological studies aimed at elucidating the mechanism of action of kappa agonists, U-50488 has been shown to depress excitatory post-synaptic potentials in a rat locus coeruleus preparation, which indicates that it acts presynaptically to inhibit transmitter release [38]. Also, in spinal cord slice preparations from the 9-16-day-old rat, U-69593 (9) produced a naloxone-reversible depression of spontaneous and electrically evoked activity in dorsal horn neurones [39],... 

Further evidence which indicates that kappa agonists may be neuropro-tective and gives insight into the possible mechanism of action is that PD 117302 (12) protects cultured rat neurons from glutamate-induced cell death [40]. 

Table 3.3. RECEPTOR BINDING AND ANALGESIC ACTIVITY OF THE ICI KAPPA AGONISTS [57,58]. 

Rhone-Poulenc have synthesized some kappa agonists which are of chemical interest because the arylacetamide fragment, which characterizes all of... 

It is a kappa agonist. It produces analgesia equivalent to nalbuphine and buprenorphine but produces more sedation. 

Dogrul, A., Yesilyurt, O., Isimer, A., Guzeldemir, M.E. L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice, Pain 2001, 93, 61-68. 

Schlaepfer, T.E. et al., Site of opioid action in the human brain mu and kappa agonists subjective and cerebral blood flow effects, Am. J. Psychiatry, 155, 470, 1998. 

Spinal sites of opioid action. Mu (v), delta (5), and kappa ( ) agonists reduce transmitter release from presynaptic terminals of nociceptive primary afferents. Mu-agonists also hyperpolarize second-order pain transmission neurons by increasing K+ conductance, evoking an inhibitory postsynaptic potential. 

In contrast to the mouse vas deferens, the guinea pig ileum contains predominately mu receptors and less kappa receptors, but no delta receptors. The function of mu and kappa receptors can be examined independently in the presence of a selective kappa antagonist (i.e., nor-BNI) and a mu antagonist (i.e., CTOP), respectively, similar to that described above for the mouse vas deferens [9]. The potency of mu and kappa agonists often exhibits higher potency in the guinea pig ileum than that obtained from the mouse vas deferens. 

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