Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents.

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).

Lipid profile of population of central region of Nepal.

This study was conducted to know the status of Lipid profile in people of central region of Nepal. This study was conducted in College of Medical Sciences & Teaching Hospital, Bharatpur, Nepal from February 2009 to March 2010 which is situated in central region of Nepal. A total of 870 cases, out of which 512(58.85%) male and 358(41.14%) female were included and study was carried out using data retrieved from the register maintained in the Department of Biochemistry. The variables collected were age, sex, lipid profile which includes total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C) & low density lipoprotein-cholesterol (LDL-C). The data was analyzed using excel 2007 and Statistical Package for the Social Sciences (SPSS) 16.0. The total mean±SD of TC, TG, HDL-C, LDL-C were found to be 164.87±49.49, 157.56±79.78, 33.59±11.10, 97.79±40.68 respectively. Total Cholesterol, HDL-C & LDL-C were found to be statistically significant whereas TG was statistically insignificant between male and female. In both male and female, TG & LDL-C were higher in the age group of 21-40 years whereas HDL-C was higher in the age group of >61 years in both the group. Total cholesterol (TC) level was higher in the age group of 21-40 years in male while in female in the age group of 41-60 years. Desirable level of TC was observed in 78.50% of the total subjects while the normal TG, LDL-C were observed in 56.55%, 81.49%, respectively. Very high levels of TC, TG, LDL-C were observed in 4.94%, 0.34% & 1.6% of the total population studied, respectively. More percentage of female (27.65%) had higher HDL-C level than in male (15.62%). High triglycerides (TG) level is the commonest lipid abnormality in our study. HDL-C level was increase with increasing in age. Clinical evaluation can be made according to this study.

The muscle relaxant activity of methaqualone and its methyl congener.

Studies with methaqualone and dimethylquinazolone showed them to possess both central and peripheral muscle relaxant activity, the latter only at high dose levels. They selectively inhibited polysynaptic reflexes and were more potent than mephenesin.

Role of catecholamines in centrogenic cardiac arrhythmia induced by aconitine.

1. Injection of 20 mug of aconitine into the lateral ventricle of dogs anaesthetized with pentobarbitone regularly induced cardiac irregularities and hypertension. The cardiovascular changes appeared within 5 min and lasted for about 90 min. Tachyphylaxis to the aconitine-induced cardiovascular effects was observed.2. The aconitine-induced arrhythmia and hypertension were centrogenic, for they were abolished or prevented by spinal transection (C(2)) or ganglionic blockade.3. Bilateral vagotomy as well as bilateral stellate ganglionectomy merely raised the threshold for arrhythmia without affecting the blood pressure response. The neural supply to the heart, therefore, does not seem to be the major pathway concerned in the genesis of the centrogenic cardiovascular effects of aconitine.4. The centrally evoked release of endogenous catecholamines from the adrenal glands was responsible for the aconitine-induced arrhythmia, since the arrhythmia could be blocked or prevented by prior reserpinization, bilateral adrenalectomy or thoracic splanchnic nerve section.5. alpha- and beta-adrenoceptive receptor blocking agents prevented or abolished the aconitine-induced arrhythmia in a manner similar to the catecholamine-induced arrhythmia.

Central adrenoceptors and cholinoceptors in cardiovascular control.

1. In cats anaesthetized with chloralose, adrenoceptor and cholinoceptor agonists and antagonists were localized to the posterior hypothalamus (PH), lateral medullary pressor area (LMPA) and spinal autonomic loci to delineate the role of central cholinoceptors and adrenoceptors in cardiovascular control. 2 All along the neuroaxis, the alpha-adrenoceptors seem to subserve an inhibitory and the beta-adrenoceptors a facilitatory role in cardiovascular control. There appear to be a predominance of alpha-adrenoceptors at the medullary level and beta-adrenoceptors at the hypothalamic level. 3 The nicotinic cholinoceptors at the hypothalamic, medullary and spinal levels were facilitatory, whereas muscarinic cholinoceptors were inhibitory for cardiovascular control. However, muscarinic receptors were undetectable at the posterior hypothalamus. 4 The central cardiovascular effects of nicotine are attributed to nicotinic receptor activation and release of central catecholamines. 5 There appears to be a relationship between central cholinergic and adrenergic mechanisms in cardiovascular control.

Involvement of central cholinoceptors in Metrazol-induced convulsions.

Atropine sulphate (10 mg/kg IP) afforded 90% protection against clonic convulsions induced by standard doses of metrazol (80 mg/kg SC) in mice, whereas atropine methonitrate (10 mg/kg IP) did not offer any protection. Furthermore, physostigmine (1 mg/kg IP) caused recurrence of convulsions in atropinzed metrazol-treated mice and converted the subconvulsive dose of metrazol (40 mg/kg SC) into a 100% convulsive dose. However, neostigmine (1 mg/kg IP) did not antagonize the protection afforded by atropine sulphate against metrazol. The results of the study suggest an involvement of central cholinergic mechanisms in metrazol-induced convulsions.

Presynaptic regulation of the release of catecholamines in the cat hypothalamus.

The posterior hypothalamus of cats was superfused through a push-pull cannula and the release of endogenous catecholamines was determined in the superfusate. Superfusion with yohimbine, isoprenaline, salbutamol or tazolol increased, while superfusion with propranolol decreased, the release of all three catecholamines. Transection of the brain caudal to the hypothalamus inhibited 'resting' and drug-induced release. It is concluded that alpha- and beta-adrenoceptors of the hypothalamus are involved in the regulation of the release of catecholamines.

An investigation into the mechanism of cardiovascular responses elicited by electrical stimulation of locus coeruleus and subcoeruleus in the cat.

Electrical stimulation of locus coeruleus (LC) and subcoeruleus (SC) elicited an increase in heart rate (HR) and blood pressure (BP). Adrenergic neurone blockade in the posterior hypothalamus with guanethidine and also bilateral adrenalectomy completely blocked the LC stimulation induced cardiovascular responses. The cardiovascular responses elicited by electrical stimulation of SC were, however, unaffected by the former and only partially inhibited by the latter. It is suggested that the LC stimulation-evoked rise in HR and BP is mediated by catecholamine release from the adrenal medulla due to an activation of the hypothalamic-adrenal axis. The cardiovascular responses elicited by stimulation of SC are mainly due to activation of the sympathetic preganglionic neurones and are further augmented by the adrenal catecholamine release.

Rise in blood pressure increases the release of endogenous catecholamines in the anterior hypothalamus of the cat.

In anaesthetized cats, anterior and posterior hypothalamic areas were simultaneously superfused with artificial CSF using two push-pull cannulae. The rates of release of endogenous catecholamines were determined in the superfusates which were continuously collected in periods of 10 seconds. In both areas, the rate of release of dopamine was higher than the rates of release of noradrenaline and adrenaline. Electrical stimulation of the splanchnic nerve elicited a rise in the arterial blood pressure and increased the rates of release of noradrenaline, adrenaline and dopamine in the anterior hypothalamic area. The rates of release of the catecholamines in the posterior hypothalamic area were not influenced by the pressor response to stimulation of the splanchnic nerve. Transection of the brain caudal to the hypothalamus reduced the rates of release of the catecholamines in the anterior hypothalamus and abolished the releasing effect of the stimulation of the splanchnic nerve. The results indicate that acute rise in blood pressure activates catecholamine cell bodies in the lower brain stem, which in turn stimulate the anterior hypothalamus to counteract the pressor response.

Involvement of alpha2-adrenoceptors of nucleus tractus solitarius in baroreflex mediated bradycardia.

Microinjections of noradrenaline and clonidine into nucleus tractus solitarius produced dose dependent bradycardia without significant decrease in blood pressure in chloralose anaesthetized cats. Phenylephrine failed to produce any significant alteration of heart rate or blood pressure. Piperoxan microinjection into nucleus tractus solitarius elicited a mild but significant tachycardia and could also block the noradrenaline and clonidine responses. Phenoxybenzamine however neither affected resting heart rate and blood pressure nor antagonized the responses of noradrenaline and clonidine. Guanethidine pretreatment of nucleus tractus solitarius also abolished the clonidine response. Baroreceptor reflex activation induced bradycardia was inhibited by yohimbine or piperoxane injected into the cisterna magna or microinjected bilaterally into the nucleus tractus solitarius. Pretreatment of nucleus tractus solitarius with phenoxybenzamine by either route, did not affect the reflex bradycardia. It is concluded that the alpha-adrenoceptors of nucleus tractus solitarius involved in the decrease in heart rate during baroreceptor activation are alpha2 in nature.

In vivo release of endogenous catecholamines in the hypothalamus.

The posterior hypothalamus of anaesthetized cats was superfused with a push-pull cannula and the release of the endogenous catecholamines noradrenaline, adrenaline and dopamine was determined in the superfusate. The rate of release of the three catecholamines followed an ultradian rhythm, the time interval between two adjacent phases of high rate of release being about 70 min. Pretreatment of the animals with reserpine decreased the levels of catecholamines in the hypothalamus and rest of the brain and reduced their rate of release into the superfusate. Hypothalamic superfusion with superfusing fluid of high concentration of potassium and low concentration of sodium enhanced the rate of release of noradrenaline and adrenaline; this effect was abolished when the hypothalamus was superfused with calcium-free solution. Electrical stimulation of the locus coeruleus ipsilateral to the superfused hypothalamus increased the release of noradrenaline and adrenaline, stimulation of the contralateral locus coeruleus enhanced the release of noradrenaline, adrenaline and dopamine. In both cases, the rate of release of adrenaline was enhanced to a lesser extent than the rate of release of noradrenaline. The release of noradrenaline and adrenaline was increased to a higher extent on stimulation of the ipsilateral locus coeruleus than on stimulation of the contralateral one.

An analysis of the alpha-adrenoceptor modulation of vasomotor tone at the level of lateral medullary pressor area (LMPA).

Microinjection of noradrenaline and clonidine into lateral medullary pressor area (LMPA) of chloralose anaesthetized cats produced dose dependent decrease in blood pressure without affecting heart rate, while phenylephrine did not elicit any cardiovascular response. Selective alpha 2-adrenoceptor antagonists idazoxan and piperoxan, microinjected locally, blocked the effects of the agonists but prazosin and phenoxybenzamine, which are relatively selective for alpha 1-adrenoceptors, failed to do so. Clonidine did not elicit any response in guanethidine pretreated cats but noradrenaline microinjected into LMPA of these animals induced a pressor response which was blocked by prazosin pretreatment. It is concluded that catecholaminergic fibres impinging upon this area inhibit the activity of the inhibitory second order baroreceptor neurone by activating alpha 1-adrenoceptors while alpha 2-adrenoceptors situated presynaptically on these inhibitory catecholaminergic nerve terminals are responsible for the manifestation of the hypotensive effect of clonidine and exogenously administered noradrenaline.

Evidence for involvement of alpha 2-adrenoceptors in the nucleus ambiguous in baroreflex-mediated bradycardia.

Microinjection of noradrenaline and clonidine into the nucleus ambiguus elicited dose-dependent bradycardia with insignificant alteration of blood pressure. Phenylephrine failed to elicit any cardiovascular effect. The bradycardic effects of noradrenaline and clonidine were antagonized by piperoxan but not by phenoxybenzamine. Adrenergic neurone blockade with local guanethidine pretreatment also abolished the response to clonidine. No significant cardiovascular effect of clonidine microinjection into the nucleus ambiguus was observed in bilaterally vagotomized animals. The baroreflex bradycardia induced by volume loading as abolished by yohimbine and piperoxan but not by phenoxybenzamine, microinjected bilaterally into the nucleus ambiguus. These results demonstrate the presence of cardioinhibitory, presynaptic alpha 2-adrenoceptors in the nucleus ambiguus and their involvement in baroreflex bradycardia.

Opioid and non-opioid central cardiovascular effects of ketamine.

The cardiovascular responses to ketamine injected intracisternally were examined in chloralose anaesthetized cats. Blood pressure and heart rate were recorded at different time intervals after intracisternal injection of drug or saline vehicle. The low doses of ketamine (0.5 or 1.0 mg) elicited dose dependent increase in blood pressure and heart rate. In contrast the high dose of ketamine (4 mg), produced a fall in blood pressure and heart rate. The cardiovascular response elicited by the low dose was naloxone insensitive and completely blocked by haloperidol, but not by dopamine antagonist pimozide. The vasodepressor and bradycardiac effect of the 4 mg dose was naloxone antagonizable. These data show that excitatory cardiovascular effects of the low dose result from a naloxone resistant site while in high doses an inhibitory effect is elicited by action at naloxone sensitive opiate receptors.

Nucleus locus coeruleus: evidence for alpha 1-adrenoceptor mediated hypotension in the cat.

Microinjection of noradrenaline or phenylephrine into the nucleus locus coeruleus of cats induced a dose dependent and long lasting hypotension. Clonidine was required in a dose of 1 microgram for eliciting a significant hypotension while its lower doses (up to 500 ng) failed to elicit any significant cardiovascular alteration. The effects on heart rate evoked by these agents were insignificant. Microinjection of alpha-adrenoceptor antagonists prazosin, piperoxan and RX 781094 per se did not evoke any significant cardiovascular effects and only prazosin pretreatment showed dose dependent antagonism of the hypotensive effect of clonidine. Piperoxan was required in four times higher dose (20 micrograms) to partially antagonize the clonidine induced hypotension. RX 781094, a selective alpha 2-adrenoceptor antagonist, however, even up to a dose of 20 micrograms (four times that of prazosin) did not alter the effect of clonidine. Similar pattern of antagonism was also seen for noradrenaline and phenylephrine. The results demonstrate the presence of alpha 1-adrenoceptors in the nucleus locus coeruleus, the activation of which leads to a fall in blood pressure.

Central alpha-adrenoceptor influence over the cardiovascular reflexes activated by veratrine.

Intravenous veratrine induced alterations in cardiovascular parameters in cats were used as a tool for assessing the influence of central alpha-adrenoceptors over reflex adjustments in the heart rate and blood pressure. Blockade of central alpha 2-adrenoceptors with idazoxan or yohimbine, inhibited, while their activation by clonidine, as also blockade of alpha 1-adrenoceptors, with prazosin, potentiated the veratrine induced bradycardia. The hypotensive effect was relatively unaltered by these treatments. Low doses of clonidine potentiated the veratrine-induced bradycardia. It appears that alpha 2-adrenoceptor mechanisms exert greater control over the reflex regulation of heart rate than over reflex control of blood pressure.

Synthesis of some newer piperazinoquinazolones as cardiovascular agents.

Twenty nine new substituted 2-methyl-3-(gamma-piperazino-propiophenyl)-4-quinazolone hydrochlorides were synthesised by the Mannich reaction of substituted quinazolones with substituted piperazines and evaluated for their cardiovascular activity. Several compounds of the series exhibited marked and sustained hypotensive activity.

New indolic hypotensive agents.

Seven substituted piperazino indoles were synthesized by the condensation of substituted piperazines with substituted indole-3-aldehyde, and evaluated for hypotensive activity. Only compound 2 exhibited promising hypotensive activity.

Biologically active substituted benzodiazepines and their effect on cardiovascular and central nervous system.

Some substituted 1,5-benzodiazepine derivatives (including a spirocyclopentane moiety) were synthesized (Table I) and evaluated for their hypotensive and CNS activities respectively. The compounds which showed promising cardiovascular activity also exhibited marked anti-depressant action (Table II,III,IV). All the compounds showed higher ALD50 value.

Cardiovascular effects of novel imidazoline congeners.

2-Aryl-4,5-bis(diphenyl)-1-(N-acetyl hydrazide)-1,3-imidazoline (IIb1-4) was prepared by the reaction of ethyl chloro acetate and hydrazine hydrate with 2-Aryl-4,5-bis (diphenyl)-1H-imidazoline (I a1-4), which on further substitution with aryl/heterocyclyl aldheyde gave 2-Aryl-4,5-bis (diphenyl)-1-(4-substituted hydrazone)-1,3-imidazoline (III Ca-i). This was again cyclised to oxadiazole in the presence of ferric chloride and glacial acetic acid yielded 2-Aryl-4,5-bis(diphenyl)-1-(2-substituted-1,3,4-oxadizole)-1,3-imi dazoline (IV da-i). These compounds were screened for hypotensive activity and an attempt were made to get the site of action of these compounds.