Synthesis and Neurotropic Activity of Novel Quinoline Derivatives

Hydroxyalkyl and carboxyalkyl derivatives of silatetrahydroisoquinoline, tetrahydroisoquinoline and tetrahydroquinoline have been synthesized. Their neurotropic activity has been investigated.


Introduction
We have shown [1,2] that the silylation increases the psychotropic activity of aminoalkanols and their salts (choline agonist/antagonist depending on the test).The mechanism of action of the silylated compounds can be stipulated by the overcoming the lipophilic barrier [3].To verify this finding we have synthesized amino acids (Scheme 1-3) and investigated their neurotropic activity and acute toxicity in comparison with organosilicon derivatives of heterocyclic aminoalkanols (3, 4, 7-9, 12, 13) [4].

Results and Discussion
Silatetrahydroisoquinoline 14 has been synthesized by the cyclization of the previously obtained dimethylchloromethyl(2-bromomethylphenyl)silane with glycine ethyl ester (Scheme 1).
Psychotropic activity of the compounds synthesized and the corresponding methiodides have been examined on mice (i.p. administration in the doses of 50 mg/kg) along the number of tests as rotating rod, tube, rectal temperature, traction, hypoxia, hexenal and ethanol anaesthesia, corazole convulsions, phenamine hyperactivity.
The majority of the studied compounds has been found to possess the sedative activity.
Comparison of aminoalkanol and amino acid derivatives has demonstrated that aminoalkanols 1-13 and amino acid derivatives 14-21 appeared to be of approximately equal potency in locomotor activity and muscle tone tests, in tests of hypoxia and hexenal anaesthesia.
Amino acids prolonged the ethanol anaesthesia, while aminoalkanols reduced it (excluding compound 9).The action of aminoalkanols was appreciable both in clonic and tonic phase of corazole convulsions test, amino acids were active only in tonic phase.Amino acids were a little more active as the phenamine antagonists.The neurotropic activity data for the most active tetrahydro [sila,iso] 18) was the most active in the test of hexenal anaesthesia, prolonging the hexenal action by 1.85 times.This compound has been found to be less toxic compound (LD 50 = 3550 mg .kg -1 ).

Conclusions
Depending on the nature of a hetetrocycle, Nsubstituent and the presence of a silicon atom in the molecule, the compounds under study exhibit a predominant psychotropic activity: tetrahydroisoquinolines show a sedative activity; the silatetrahydroisoquinoline derivatives -an antihypnotic action (shortening of ethanolinduced sleeping time); tetrahydroquinolines anticonvulsant (pentylenetetrazol-convulsion test) effects.
The data obtained indicate a usefulness of rational design for novel neuroprotective compounds in a series of the silicon-containing heterocyclic derivatives.

General methods
Melting points were determined on a Boetius table and were uncorrected.NMR spectra were obtained on a Bruker WH-90/DS spectrometer operating at 90 MHz using CDCl 3 and DMSO-d 6 as solvents and Me 4 Si as internal standart.IR spectra were recorded for nujol mulls on a Perkin-Elmer 580B spectrometer.GLC analysis was conducted on a Chrom-42 instrument equipped with a flame-ionization detector using a glass column (1.2m x 3 mm) packed with 5% OV-17 on Chromosorb W-AW (60-80 mesh).

Pharmacological methods
The neurotropic activity of the synthesized compounds was studied on BALB/c mice of both sexes weighing 18-23 g in winter season.The room temperature was maintained within the limits 21 + 2 o C. Solutions of compounds in olive oil or aqueous suspensions of the remaining substances, prepared with the addition of Tween-80, were introduced intraperitoneally 30-45 min (the oily solutions 60 min) before the test.The same volume of the sodium chloride isotonic solution was injected into the control animals.The effect of the substances injected in the doses of 50 mg/kg was compared in groups of animals, consisting of 6-8 individuals.The experimental data were treated statistically.The mean values of LD 50 and ED 50 for 12-25 observations were determined by a rapid method given in [11].The arithmetical means and their standard deviations (M±m) were calculated to assess the average duration of the anaesthetic effect of the hexenal and phenamine stereotypy, the protective properties in the corazol spasms and hypoxia, the degree of hypothermia.The significance of differences between mean values were assessed by Student's criterion: differences were considered as significant at a probability level p < 0.05.
The effect of the substances on the central nervous system was estimated: -from their influence on the coordination of movements and the muscle tone by the tests "rotating rod"(8rpm for 2 min on an Ugo Basile apparatus), "tube" (30 x 2 cm glass tube, 30 sec), and "tightening in crossbeam" (2 mm metal wire, 5 sec); -from the influence on the body temperature: by measuring the rectal temperature with an electric thermometer (the criterion for the test was a lowering of the temperature by 3 o C and more); -from the analgesic effect, determined by the "hot plate" method; -from the antispasmodic activity, estimated by the maximum electric shock test (a.c.current with an intensity of 50 mA and a frequency of 50 pulses/sec, duration of stimulation 0.2 sec); -from the corazol spasms caused by the intravenous titration with 1% corazol solution at a rate of 0.01 ml/sec; -from the influence on the duration of the hexenal anaesthesia (70 mg/kg, i.v.) and the ethanol anaesthesia (25% solution of ethanol i.a., the dose of 5 g/kg); -from the influence of the life time of animals under hypoxic hypoxia, created by placing the mouse in a separate chamber with a volume of 220 cm 3 without absorption of CO 2 ; -from the the change in the locomotor activity, enforced by phenamine (10 mg/kg, s.c.).
The acute toxicity was determined by the intraperitoneal introduction of the investigated substances and by establishing the lethal dose (LD 50 ).