Antagonists opioid morphine derivatives

It is worth mentioning that iV-allylic substitution in a number of morphine derivatives, as a rule, leads to antagonistic properties. Naloxone is a few times stronger than nalorphine as an antagonist. It blocks opiate receptors. It eliminates central and peripheral action of opioids, including respiratory depression. Naloxone is used upon overdose of narcotic analgesics.Synonyms for this drug are narkan, talwin, and others. 

The pure opioid antagonist drugs naloxone,naltrexone, and nalmefene are morphine derivatives with bulkier substituents at the l l17 position. These agents have a relatively high affinity for - opioid binding sites. They have lower... 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Apomorphine, a derivative of morphine, acts directly on the CTZ. It also is more effective if water is first administered before oral or subcutaneous dosing. Excessive dosage may cause respiratory depression and circulatory collapse. Opioid antagonists such as naloxone usually reverse the depressant actions of apomorphine. Because of the possibility of respiratory depression, apomorphine is infrequently used as an emetic. 

The A -allyl derivative nalorphine (3-2) is prepared from A -demethylmorphine (3-1) by alkylation with allyl bromide [2]. The discovery that this compound proved to antagonize the activity of morphine in experimental animals led to the synthesis of the potent opioid antagonist naloxone (8-3), which is discussed below. Nalorphine (3-2), in marked contrast to the latter, does show some modest analgesic activity in humans. 

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. 

Buprenorphine is derived from thebaine. It is a partial mu agonist with kappa antagonist activity. Buprenorphine has 25 to 50 times the potency of morphine. It is used to produce a longer-lasting analgesia than morphine. Effects of buprenorphine last longer because it is released more slowly from mu receptors than morphine. It is available as an injectable for intramuscular (IM) or intravenous administration in a 1-ml solution containing 0.3 mg buprenorphine (as buprenorphine HC1) for the relief of moderate to severe pain. It is also available to treat opioid dependence in the formulation of a tablet,51 alone or in combination with naloxone, in 2- or 8-mg... 

Chlornaltrexamine (/f-CNA, 15) another naltrexone derivative modified at C-6, is a nonequilibrium antagonist which blocks irreversibly the three major opioid receptor types (ji, k and 8). Portoghese and his collaborators have developed this compound as the first affinity labelling agent of its class [58-61]. Compound (15) has an alkylating function at C-6 (classic nitrogen mustards) able to bind covalently to opioid receptors. In the tail flick assay in mice, /f-CNA inhibited morphine-induced antinociception for 3-6... 

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