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The signs and symptoms due to extrapyramidal tract involvement are amongst the most common side effects in tranquillizer therapy, which is uniformly present in all the six group of drugs used in medicine (1). With many of these drugs, severe extrapyramidal symptoms are uncommon, but with those phenothiazines which contain a piperazine moiety in their side chain such untoward effects are the rule rather than exception ; e.g. trifluoperazine, prochlorperazine and perphenazine. Since these are the valuable drugs in psychiatry, control of their f .trapyramidal side effects offers an important challenge. Several intriguing views, regarding the relationship of tranquillizing activity and extrapyramidal reactions are reported in literature. Freyhan (2), Brune et al. (3) and Haase (4) are of the opinion that the ability of a drug to induce parkinson like syndrome bears a positive correlation with its therapeutic efficacy, and that the fine motor extrapyramidal reactions are “conditio sino qua non” for the essential efficacy of neuroleptic drugs. Conversely, Cole and Clyde (5), Brooks (6) and Hollister (1), believe that the suppression of parkinsonism does not lead to the impairment of therapeutic efficacy of tranquillizers and that the clinical appearance of extrapyramidal syndrome in no way predicts the therapeutic response of a tranquillizer. An endeavour to find out the inter-relationship of parkinsonism and antipsychotic activity of tranquillizers can profitably be made by taking the hypothesis of McGeer et al. (7) into consideration. According to these suggestions, there is an equilibrium within the brain between the two groups of biogenic amines: serotonin-catecholamine on one hand, while acetylcholine-histamine on the other. Parkinsonism is characterized by an imbalance between these two systems and can be corrected either by increasing the neurohumoral content of one system or by decreasing that of the other. Since the therapeutic efficacy of phenothiazine group of tranquillzer bears a close correlation with their antiserotonin (8) and antiadrenergic (9) activity, the two possible ways to inhibit parkinsonism, without interfering with antipsychosis, could be to enhance their antihistaminic or antiacetylcholine action. But potent antihistaminics amongst phenothiazine series e.g. promethazine, or ethopropazine possess little tranquillizing activity, while perphenazine and trifluoperazine which are weak antihistaminic are on the other hand potent tranquillizers. Therefore, the only way to reduce their parkinsonism liability is to increase their antiacetylcholine like action. Since oximes are well known as antidotes for organophosphorous poisoning (anti DFP), we speculated that anticholinergic quaternary oximes of phenothiazine drugs can provide a tranquillizer with lesser liability of extrapyramidal reaction and that the study with these compounds is likely to furnish certain clues for the inter-relationship of thses two actions, one desirable and the other unwanted.

PHARMACOLOGICAL STUDIES WITH SOME NEWLY SYNTHESIZED PHENOTHIAZINES EXHIBITING LESSER EXTRAPYRAMIDAL REACTIONS