Antagonists morphine

This derivative is one of the most potent morphine-antagonists yet examined (19 X nalorphine in rats [221]) and it gives no analgesic response in the mouse hot-plate and rat tail-flick tests [222]. It is inactive, furthermore, in the mouse... 

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. 

Blane G.F. and Boura A.L. Analgesic and other actions of morphine antagonists, Naunyn Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1968, 259, 154-155. 

Thebaine (Figure 6.50) differs structurally from morphine/codeine mainly by its possession of a conjugated diene ring system. It is almost devoid of analgesic activity, but may be used as a morphine antagonist. Its main value is as substrate for the semi-synthesis of other drugs (see below). 

Therapeutic Function Respiratory stimulant, Barbiturate antagonist, Morphine antagonist... 

A considerable extension of the duration of activity together with a strongly reduced toxicity has been found (79) for a preparation with morphine-antagonistic activity [7 7 the place of its action being localized also in the central nervous system. Hie possibility of cleavage is in this case attributed to the activated ester, bound between the polymeric chain and the active substance. Besides the above-mentioned derivative of acrylic acid a derivative of vinyl carbamate has also been applied. 

Figure 2.3 Dextromethorphan 6, the unnatural enantiomer of a narcotic morphine analog, is an antitussive drug. The antidiarrhea drug loperamide 7 and the neuroleptic drug haloperidol 8 also resulted from structural modification of morphine. The morphine antagonist nalorphine 9 differs from the opioid agonist morphine 3 (Figure 2.2) only by having an N-allyl group instead of the N-methyl group.

N-Allylnormorphine (Nalorphine) was prepared(143) in impure form<144) in 1941 for evaluation as an analgesic with low respiratory depression properties, but powerful morphine antagonist activity was observed, and subsequently this has been exploited extensively in the clinic/144,145 ... 

Unfortunately, in a series such as this, antagonists have not yet been discovered with the potency to match agonists. Diprenorphine is about 100 x nalorphine as a morphine antagonist, and it exhibits no antinociceptive properties in the MW test. 339 However, in the GPI assay, some agonist actions were... 

Hydroxy-N-cyclopropylmethylmorphinan proved to be not only a powerful morphine antagonist (AD50, 0.03 mg/kg v. pethidine) that is about four times the potency of nalorphine, but was also a very effective analgesic in humans. As we now expect for compounds bearing - antagonist substituents, very little antinociceptive activity was observed in most rodent assays, (e.g., RTF) under standard conditions. 

As indicated in Table 22-2. replacement of the A/-mcthyl group in morphine by larger alkyl groups not only lowers analgesic activity, but also confers morphine-antagonistic properties on the molecule (discussed below). In direct contrast to this effect, the A7-phenethyl derivative has 14 times the analgesic activity of morphine. This enhancement of activity by )V-aralkyl groups has wide application, as is shown below. 

I ng of morphine using an electrode potential of +0.60V (vs. silver/silver chloride reference electrode (SSCE)). Several authors reported the use of commercially available electrochemical detectors for the analysis of morphine and some morphine antagonists, electrode potentials of +1V69, +0.8V70, +0.725111, +0.79112 and +0.6-0.8V115 (all vs. 

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