The relation between the chemical structure and pharmacological activity of some esters of 3-hydroxyquinuclidine(qulnuclidine-3-ol)

Abstracts

THE

RELATION

BETWEEN

PHARMACOLOGICAL

THE

227

CHEMICAL

ACTIVITY

3-HYDROXYQUINUCLIDINE

STRUCTURE

AND

OF SOME ESTERS OF

(QUINUCLIDINE-3-OL)

M. D. MASHKOVSKY Laboratory

of Pharmacology,

Pharmaceutical

All-Union

Research Institute,

Chemical-

Moscow, U.S.S.R.

THE pharmacological properties of a group of 3-hydroxyquinuclidine or quinuclidine-3-01 esters formed with some fatty, aromatic, fatty-aromatic and heterocyclic acids, as well as carbamates and quaternary salts of these esters have been studied in our laboratory. The preparations were synthetized by RUB~OV et al. (1960) and MICHLINAand RIJBTSOV(1960). Among the esters of 3_hydroxyquinuclidine, as well as 3-hydroxymethyl- and 3-hydroxyethylquinuclidine, with fatty acids the most interesting one is 3-acetohydryroxyquinuclidine named aceclidine. This compound possesses a strong cholinomimetic action (MASHKOVSKYand ZAJTSEVA,1960). The intravenous injection of aceclidine induces a pronounced fall of arterial blood pressure and a slowing of the heart in the anaesthetized cat or dog. The hypotensive action appears beginning with the injection of 0.05-0.1 pg/kg. It also causes bronchospasm, contraction of intestines and the bladder, miosis and other effects characteristic of substances with cholinomimetic, predominantly muscarine-like activity. After the administration of this drug the electroencephalogram shows a typical “ arousal reaction “. All these responses were abolished by atropine. The cholinomimetic action of aceclidine is intimately connected with the presence of the quinuclidine nucleus in its molecule. In case quinuclidine is substituted by 3-methyl-piperidine, which is closely related to quinuclidine in structure, the activity is greatly diminished. The pharmacological activity of aceclidine also depends on the presence of the tertiary nitrogen atom in its molecule; indeed, the corresponding quatemary salt is about 200 times less active than aceclidine. The esters of 3-hydroxyquinuclidine with larger substituents than the acetic acid radical (e.g. esters with propionic, butyric or isovalerianic acids) do not possess any cholinomimetic activity: on the contrary, they are weak cholinolytics. As to the carbamates, corresponding to aceclidine, they possess a rather low activity. Methiodide of 3-dimethyl-carbamyl-hydroxyquinuclidine has a weak nicotine-like and anticholinesterasic activity; it is about 2000 times less active than neostigmine. The 3-hydroxymethylic analogue of aceclidine is nearly as active as aceclidine whereas the corresponding ethylic compound is less active. Among the esters of 3-hydroxyquinuclidine with aromatic and heterocyclic acids which have been studied the most interesting one is 3-benzoylhydroxyquinuclidine or I‘ oxylidine.” This compound possesses a moderate cholinolytic, adrenolytic, hypotensive and sedative action. The introduction of substituents (Cl, Br, NH,, NO,, OCH,) in the benzene ring diminishes the activity. In the group of the esters of 3-hydroxyquinuclidine with fatty-aromatic acids (phenylacetic, phenoxyacetic, phenylpropionic, etc.) the most active is the diphenylpropionic ester or “aprolidine” which has a strong cholinolytic action. In structure and pharmacological properties this compound resembles the diphenyl acetic ester of quinuclidine-3-01 studied by RANDALLef al. (1960). The esters of 3-hydroxy 3-alkyl(aryl)quinuclidine have no apparent cholinomimetic, cholinolytic, adrenolytic, hypotensive or sedative activity. REFERENCES MICHLINA,E. E. and RUBTSOV,M. V., (1960). Jurnal obshtshej chimii. 30: 163. MASHKOVSKY,M. D. and ZAJTSEVA,K. A. (1960). KaPMaKOROLNR N. TOKCNKOFOLNR.Pharmacol. Toksikol23:

398.

RANDALL,L. O., BENSON,W. M. and STEFKO,P. N. (1952). J. Phartnacol. 104: 284. RUBTSOV,M. V., MICHLINA, E. E. and YACHONTOV,L. N. (1960). Uspiechy chimii 1: 74.