Naltrexone selectivity

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

Herman, B.H., Asleson, G.S., Borghese, I.F., Chatoor, I., Powell, A., Papero, P., Allen, R.P., and McNulty, G. (1991) Acute naltrexone in autism selective decreases in hyperactivity. In Proceedings of the 38th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. San Francisco AACAP. 

As mentioned earlier in the chapter, in the UK lofexidine is far more frequently selected in opiate detoxification than clonidine because of its better safety for outpatients, and a large comparative study of this and buprenorphine was carried out by Raistrick et al. (2005). Two hundred and ten patients were randomized, and the same comparisons in standard drug misuse outcomes and satisfaction measures were also studied in 271 individuals who did not wish to be in the randomized study. Many outcomes were similar with the two medications, but 65% of buprenorphine patients completed detoxification against 46% of those on lofexidine. That study was an example of one which included a follow-up to see whether patients had been abstinent after detoxification, with this being the case at the measurement point of one month for 38% of lofexidine completers and 46% with buprenorphine. This important aspect of whether successful detoxification does indeed lead to further abstinence has attracted attention in several buprenorphine studies, as reviewed by Horspool et al. (2008). Across five qualifying studies, they found detoxification completion rates of 65 to 100%, but low rates of abstinence at follow-up points, with more patients having returned to opioid maintenance than had complied with naltrexone. 

One of the studies of the greatly increased death rate of recently released addict prisoners (Farrell Marsden 2008) had as a conclusion that there must be planned referral to community-based treatment services . Coming full circle, in our main service we offer first-day appointments for released prisoners from our area to continue their substitution treatment, or naltrexone in cases where that has already been selected by a user and started. 

Myers RD, Borg S, Mossberg R. Antagonism by naltrexone of voluntary alcohol selection in the chronically drinking macaque monkey. Aicohoi 1986 3 383-388. 

Methyinaltrexone is a quaternary derivative of the opioid antagonist, naltrexone. The addition of the methyl group forms a compound with greater polarity and lower lipid solubility, so that it is poorly absorbed, and does not cross the blood-brain barrier. Methyinaltrexone distributes selectively (>200-fold selectivity) to peripheral receptors. In human trials it prevented morphine-induced delay in gastrointestinal transit time, while sparing centrally mediated analgesic effects. 

Opioid receptor binding Naltrexone has a high affinity and selectivity for the p-opioid receptor (Hollt and Herz, 1978). 

It was found that only one pharmacophore is required for the k opioid antagonist selectivity of nor-BNI [136]. In smooth muscle preparations, the meso isomer (81) (derived from (-)-naltrexone and its inactive (+)-enantio-mer [27]) of nor-BNI was more potent than nor-BNI and about half as selective as k antagonist. Since (81) contains one antagonist pharmacophore but yet retains some k selectivity, it was concluded that k selectivity is not de-... 

The rationale for the design of naltrindole (NTI, 82) by Portoghese and his collaborators [170] was based on the message-address concept [171, 172], This design strategy for nonpeptide 8 selective antagonists employed the naltrexone pharmacophore for the message moiety and a key element in the leu-... 

Introduction of 14/ -ethoxy and 5/ -methyl groups into the NTI molecule resulted in the pure opioid antagonist (121) with somewhat lower S potency but much higher 5 selectivity in the MVD due to very low fi and k affinities (Table 3.11) [191]. Indole (121) was prepared by reacting the fi receptor-preferring opioid antagonist 14-O-ethyl-5-methyl naltrexone [192] with phenyl-hydrazine under conditions used for the Fisher indole synthesis. 

Naltrexone (t) 4 h active metabolite 13 h) is similar to naloxone but longer-acting, with duration of effect 1-3 days according to dose. It can be used orally to assist in the rehabilitation of ex-opioid abusers who are fully withdrawn (otherwise it will induce an acute withdrawal syndrome). A patient who then takes an opioid fails to experience the kick or euphoria, although naltrexone does not reduce craving as does the agonist methadone. This use of naltrexone requires careful selection and supervision of subjects. 

The combined use of clonidine and naltrexone appears to allow successful withdrawal from long-term methadone therapy within 4-5 days of its abrupt withdrawal. Although patient selection may be an important consideration, the apparent success rate compares favorably with other methods and is achieved in a much shorter time (70). 

Takemori. A.E. etal (1992) Selective naltrexone-derived opioid receptor antagonists. Anna. Rev. Pharmacol. Toxicol. 32.239-269. 

Opioid antagonists (Table 7.4), predominantly naloxone, are used clinically to reverse the effects of opiates in overdose or postoperative sedation. Naltrexone, which has oral bioavailability, is used for the treatment of narcotic addiction and alcohol dependence. As discussed below (Section 2.2.2.1), peripherally selective antagonists are being evaluated for treatment of constipation and other gastrointestinal side effects associated with opioid agonist use. 

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