Rational design, synthesis and evaluation of (6aR( *),11bS( *))-1-(4-fluorophenyl)-4-{7-[4-(4-fluorophenyl)-4-oxobutyl]1,2,3,4,6,6a,7,11b,12,12a(RS)-decahydropyrazino[2',1':6,1]pyrido[3,4-b]indol-2-yl}-butan-1-one as a potential neuroleptic agent.

In our pursuit to prepare a potent antipsychotic compound, a novel 1,2,3,4,6,6a,7,11b,12,12a-decahydropyrazino[2',1':6,1]pyrido[3,4-b]indole derivative was synthesized which incorporates the butyrophenone substructure twice. This molecule has shown D(1), D(2) and 5-HT(2A) receptor blocking activity where the ratio pK(i) (5-HT(2A)) to pK(i) (D(2)) is 1.42 better than risperidone (1.15). It blocks amphetamine induced hyperactivity/stereotypy and secondary conditioned avoidance responses in rodents at lower doses than those required for the neuroleptic drugs haloperidol and centbutindole (biriperone).

Peptidergic mechanisms in feeding behaviour.

Hyperphagia was induced in mice by p.o. administration of different types of CNS depressant drugs, like chlordiazepoxide 25 mg/kg diazepam 2.5 mg/kg, cyproheptadine 2 mg/kg and phenobarbitone 25 mg/kg. Such hyperphagia was abolished by pretreatment with naloxone 0.1 mg/kg sc. Naloxone per se at this dose produced no significant effect on the food intake. This is suggestive of the role of peptidergic mechanisms in the feeding behaviour in mice.

p-Aminobenzene sulphonyl morpholine, compound 82/208 a new anticonvulsant agent.

p-Aminobenzene sulphonyl morpholine, compound 82/208, was evaluated for acute toxicity and anticonvulsant action in mice against tonic seizures induced by supramaximal electroshock and pentylene tetrazole and strychnine induced seizures and for its effect on blood pressure and respiration in cat. Diphenyl hydantoin (DPH) was used as reference standard. Compound 82/208 exhibited anticonvulsant activity against electroshock induced seizures and PTZ induced tonic seizures in mice. The compound had several distinct advantages over DPH in experimental evaluation in mice.

Studies in hypotensive agents. Synthesis and hypotensive activity of 3,4-dihydro-1(2H)-benzoxepine oxime ethers and their derivatives.

Substituted oximino-ethers of 3,4-dihydro-1(2H)-benzoxepines were synthezised from 3,4-dihydro-1(2H)benzoxepin-5-ones. The hypotensive activity of these compounds was evaluated on anaesthetized cats.

Syntheses and biologic studies of steroidal methyl sulfides and sulfones.

Reactions of cholest-5-ene (I) and its 3 beta-chloro (II) and 3 beta-acetoxy (III) analogs with trimethylchlorosilane-dimethyl sulfoxide in dry acetonitrile furnish cholest-4-en-6 beta-yl methyl sulfide (IV) and its 3 beta-chloro (V) and 3 beta-acetoxy (VI) analogs. Oxidation of (IV) with m-chloroperbenzoic acid affords cholest-4-en-6 beta-yl methyl sulfone (VII) and 4 alpha, 5-epoxy-5 alpha-cholestan-6 beta-yl methyl sulfone (VIII). Under similar reaction conditions, V furnishes 3 beta-chlorocholest-4-en-6 beta-yl methyl sulfone (IX), while VI gives 3 beta-acetoxycholest-4-en-6 beta-yl methyl sulfone (X) and 3 beta-acetoxy-4 alpha, 5-epoxy-5 alpha-cholestan-6 beta-yl methyl sulfone (XI). The structures of these compounds were established on the basis of analytic and spectral data. Some of these compounds have been evaluated for their possible biologic activities.

Adaptogenic activity of Indian Panax pseudoginseng.

The crude extract and saponins of Indian pseudoginseng and saponins of Korean ginseng have been studied using a battery of biological tests in rats and mice. Indian pseudoginseng saponins were found to exhibit better activity than the Korean ginseng saponins in several tests employed. The results indicate a need for in-depth study of Indian pseudoginseng as an adaptogenic agent, after cultivation of the plant under controlled conditions.

Synthesis and pharmacological evaluation of some 2-N-alkyl-and -aralkyl-3,4:6,7-dibenzomorphans.

2-N-Alkyl or 2-aralkyl-5,9-dimethyl-3,4:6,7-dibenzomorphans 3a-c were synthesized by condensing 1-alkyl or aralkyl-3,4-dimethylquinolinium iodides 1a-c with benzyl magnesium chloride followed by subsequent cyclization of 2-benzyl-1-alkyl or aralkyl-3,4-dimethylquinolines 2a-c. Their structures were established through elemental and spectral studies. The preliminary pharmacological screening of 3a-c and other 3,4:6,7-dibenzomorphans [16] on mice showed that these compounds have a depressant action on CNS.

Synthesis of N-aryl-N'-[2-phenyl-3-quinazoline(3H)-4-one] acylthiourea derivatives as anticonvulsants.

By the reaction of [2-phenyl-3-quinazolineo (3H)-4-one] acyl isothiocynates and appropriate aryl amines in acetone, 24 new compounds, having a substituted thiourea grouping at the 3-position of the quianozolone moiety, were prepared. All compounds, except two, showed different degree of protection against pentetrazol induced seizures test in albino mice. While studying the effect of structural variation no definite pattern could be observed due to variations in 1-aryl moiety, but it was noticed that generally the branching or lengthening of 3-acyl chain either diminishes or does not effect the activity.

Synthesis of some 2,3-disubstituted quinazolones as possible anticonvulsants.

By the condensation of 2-phenyl-3-acylchloride quinazolin (3H)-4-one with N-phenyl- and N-methyl piperazines or piperidine, 15 new 2-phenyl-3-piperidino/substituted piperazino acyl-quinazolin (3H)-4-ones 1--3 have been prepared. All the compounds barring one exhibited at the 100 mg/kg dose level significant activity against pentylenetetrazol induced seizures but these compounds did not afford any protection against electroshock induced seizures.

Evidence for the presence of -adrenoceptors in the central thermoregulatory mechanism of rabbits.

1. The effects of intracerebroventricular administration of some alpha- and beta-adrenoceptor stimulants and antagonists on the body temperature of rabbits were investigated.2. Noradrenaline produced a dose dependent rise in body temperature. Other catecholamines were less active.3. The noradrenaline response was blocked by alpha-adrenoceptor blocking agents while beta-adrenoceptor antagonists had no effect.4. alpha-Methyl-noradrenaline and metaraminol had some hyperthermic effect, but significantly reduced the response of noradrenaline.5. The possible presence of alpha-adrenoceptors in the central thermoregulatory mechanisms is suggested.