Opioid receptors agonist-antagonists/partial agonists

The biggest challenge is the treatment of addiction itself. Several approaches have been proposed, but all remain experimental. One approach is to pharmacologically reduce cravings. The P-opioid receptor antagonist and partial agonist naltrexone is FDA-approved for this indication in opioid and alcohol addiction. Its effect is modest and may involve a modulation of endogenous opioid systems. 

The treatment of opioid abuse and dependence aims also at preventing the social complications of abuse, especially infections linked to parenteral administration (HIV and HepB). It relies on the use of substimtive drugs that can be either pure agonists, or partial agonist-antagonists (methadone, buprenor-phine, naltrexone), with the objective of limiting receptor desensitization and the development of tolerance. Any success in the treatment of opiate dependence may stem as much from the re-establishment of healthcare contact and social reinsertion as from any treatment induced decrease in the abuse behaviour itself. 

Bot G, Blake A, Li S, Reisine T. Mutagenesis of a single amino acid in the rat mu opioid receptor discriminates the binding of full agonists from partial agonists and antagonists. J Neurochem 1998 70 358-365. 

Bot, G, Blake, A, Li, S, Reisine, T. Mutagenesis of the mouse delta opioid receptor converts - buprenorphine from a partial agonist to an antagonist. J Pharmacol Exp Ther 1998 284 283-290. 

The answer is c. (Hardman, p 546.) Pentazocine is a mixed agonist-antagonist of opioid receptors. When a partial agonist, such as pentazocine, displaces a full agonist, such as methadone, the receptor is less activated this leads to withdrawal syndrome in an opioid-dependent person. 

Partial agonists and antagonists compete with agonists for opioid receptor sites and exhibit mixed agonist-antagonist activity. They may have selectivity for analgesic receptor sites and cause fewer side effects. 

Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy. 

The antagonist action of partial agonists may result in an initial decrease in effect of a full agonist during changeover to the latter. Intoxication with buprenorphine cannot be reversed with antagonists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the receptors cannot be achieved as fast as the clinical situation demands. 

Table 2. Agonists, antagonists and partial agonists for the various opioid receptors...

Opioid receptor binding Butorphanol (Rosow, 1988) is a mixed agonist-antagonist opioid with full agonistic activity at the K-receptor and partial agonistic-antagonistic effect at the p-receptor. The compound has a high p- and k-receptor affinity. 

Opioid receptor binding Pentazocine (Brogden et al., 1973) is a mixed opioid agonist-antagonist with agonistic effects at the kappa and partial antagonistic effects at the p-type of opioid receptor. 

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