Pharmacological studies on alicyclic amines. I. Comparison of pharmacological activities of piperidine with those of other amines.

Abstract

In a study of structure-activity relationship in antitussive agents, a working hypothesis has been presented that introduction of piperidino group into a compound showing any actions on the central nervous system, can produce antitussive activity if the activity has been latent, or strengthen it if such activity is already manifest (1, 2). In order to clarify this mechanism, piperidino and other alicyclic amino compounds such as pyrrolidino, morpholino and piperazino, and aliphatic amino compounds such as n-amylamino, iso-amylamino, diethylamino, and dimethylamino compounds possessing the same residues were synthesized and the following pharmacological activities of those compounds have been investigated: Toxicity, analgesia, local anesthetic action, potentiation and prolongation of anesthetic action, respiratory depressant action in vivo, inhibitions of succinic dehydrogenase and respiration of brain tissue. However, any significant differences have not been found between the pharmacological properties of piperidino compounds and those of other alicyclic and aliphatic amino compounds. Therefore, piperidine from which piperidino group originated has been compared with other alicyclic and aliphatic amines such as pyrrolidine, morpholine, piperazine, amylamines, diethylamine and so forth, from which the corresponding amino groups originated, in order to find a clue to differentiate pharmacological properties between the two. Having compared the peripheral and central actions of alicyclic amines, especially piperidine with those of aliphatic amines, the authors found that there were fundamental differences between the two, that piperidine in alicyclic amines had pronounced actions similar to nicotine, and that pyrrolidine also had almost the same pharmacological activities as those of piperidine, while aliphatic amines never showed such pharmacological actions. Since piperidine, possessing nicotinic properties, has been said to be one of normal constituents in human urine (3, 4) and mammalian brain (5), it seems to be of great interest to study the physiological role of piperidine in the living body. It has been seemed to the authors that piperidine might be an endogenous synaptotropic agent as Euler (6) had stated before, serving some neural function in the regulation of behavior. The more so, after the authors had found its cholinergic and synaptotropic properties in the central nervous system (this finding will be shown in the succeeding report in the near feature). The present paper deals with experimental observations, giving priority to piperidine, on the peripheral actions of alicyclic and aliphatic amines and shows a conspicuous pharmacological activity of piperidine among the amines used.