PHARMACOLOGICAL PROPERTIES OF BENZAZOLES I. RELATIONSHIP BETWEEN STRUCTURE AND PARALYZING ACTION

¹ Department of Pharmacology, University of Illinois College of Medicine, Chicago 12, Illinois and the Research Division of Smith, Kline and French Laboratories, Philadelphia 1, Pennsylvania

An isosteric series of benzazoles was compared for their ability to produce paralysis in animals of various species.

1. The effects produced by the benzazoles were a mixture of stimulation and depression. The stimulating effects were usually the first to occur, and subsequently were followed by the depressant effects which were predominant.

2. The substituted 2-aminobenzothiazoles in particular were paralyzing agents of high potency. Methyl or chloro groups substituted in the benzene ring of 2-aminobenzothiazole produced depression according to the following order of substitution: position 6 > 5 > 4 > 7. 6-Methyl-2-aminobenzothiazole was especially free of any stimulating effects.

3. A 1 or 2 carbon alkyl chain in position 2 of the benzazole had no marked effect on potency but caused more respiratory depression, while lengthening the alkyl chain to amyl produced a convulsant. The azole ring structure appeared essential for the paralyzing properties of the benzazoles. Opening the azole ring of 2-aminobenzothiazole as in phenylthiourea produced a convulsant. The heterocyclic ring could be 5-membered as in a benzazole or 6-membered as in quinoxaline in order to produce paralysis. Tautomerism in the azole ring was apparently one requirement for high paralyzing potency in this series of benzazoles.

4. None of the benzazoles had any curare-like action in doses producing paralysis. While some benzazoles produced local anesthesia, and on intravenous administration hemolysis of erythrocytes, their local anesthetic and also their hemolytic properties did not correlate with their ability to produce paralysis. 6-Methyl-2-aminobenzothiazole produced a transient drop in blood pressure when given rapidly intravenously, while slow intravenous administration or oral administration had little effect. This agent produced central respiratory depression before affecting the vasomotor centers.