The Prevention by Sulphydryl Compounds of the Toxicity in the Cat of 2,6‐dimethoxyphenol and Its Morpholinopropionyl Ester

Abstract

Intravenous (—)‐2,6‐dimethoxyphenyl‐2‐morpholinopropionate hydrochloride (M&B 16,573) produced anaesthesia of short duration in the mouse, rat, rabbit, cat, dog and monkey. In the cat but not in other species, a severe and usually fatal toxic reaction was seen 1‐2 h after administration. This toxic reaction but not the anaesthetic properties of M&B 16,573 was prevented by the intravenous administration of cysteine or N‐acetylcysteine. Cysteamine or dimercaprol were ineffective. Intravenous administration of 2,6‐dimethoxyphenol or 2,6‐dimethoxyquinol in the cat produced a response similar to the delayed toxic effects of M&B 16,573 but not preceded by anaesthesia. The toxic effects of these compounds were prevented by cysteine. Intravenous 4‐allyl‐2,6‐dimethoxyphenyl‐2‐morpholinoprop*ionate hydrochloride produced anaesthesia in the cat without the delayed toxic effects seen after M&B 16,573. The acute toxicity of 2,6‐dimethoxyquinol in mice was reduced by the administration of cysteine or N‐acetylcysteine. It is postulated that the delayed effects produced by M&B 16,573 in the cat are due to the formation of 2,6‐dimethoxyquinol and 2,6‐dimethoxybenzoquinone in this species, the toxicity of the latter being reduced by sulphydryl compounds.

α-Amino Acid Phenolic Ester Derivatives: Novel Water-Soluble General Anesthetic Agents Which Allosterically Modulate GABAA Receptors

“…Nevertheless, the realization that introduction of this methyl substituent afforded derivatives with a reasonably good anesthetic profile was important since a quinol metabolite of the lead 1 had been shown to be toxic in cats and the para substituent could prevent formation of such a metabolite. 10 With regard to modification of the amino substituent, saturated heterocyclic derivatives tend to produce side effects or marked toxicity whereas retention of a double bond or incorporation of a heteroatom affords compounds with a good anesthetic profile. 3 Thus the tetrahydropyridinyl derivative 12 exhibited reasonably good in vitro and in vivo activity.…”

“…The introduction of a p -methyl group on the aromatic ring, e.g., compound 11 (HD 50 = 68.0 μmol/kg), caused a reduction in in vivo potency, and the time to onset of anesthesia was marginally slower than for the unsubstituted analogue 10 . Nevertheless, the realization that introduction of this methyl substituent afforded derivatives with a reasonably good anesthetic profile was important since a quinol metabolite of the lead 1 had been shown to be toxic in cats and the para substituent could prevent formation of such a metabolite …”