STEREOSELECTIVITY IN CENTRAL ANALGESIC ACTION OF TOCAINIDE AND ITS ANALOGS

The antiarrhythmic drug tocainide (5a) and some related chiral alpha-a mino and alpha-imino anilides (5b-e) were synthesized in optically act ive form. The antinociceptive effects of the different stereoisomers o f these compounds were examined and it was found that the analgesic ef fect of tocainide is due only to its (-)-(R)-enantiomer. Benzyl replac ement for methyl group at the stereogenic centre of tocainide causes l oss of activity while both enantiomers of the alpha-iminoxilidide 5e a nd of the strictly related tocainide analog 5d produce an analgesic ef fect without any stereoselectivity. Pharmacological tests and [H-3] qu inuclidinyl benzilate ([H-3]QNB) binding assay, taken together, seem t o show that the antinociceptive effect of (-)-(R)-tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action.