Synthesis and pharmacological study of some new octahydroquinazoline derivative as hypotensive agents

New 1,2,3,4,5,6,7,8-octahydro-5-oxo-1-[4-substituted phenyl]-3-substituted phenylquinazolines and their 7,7-dimethyl derivatives were prepared through Mannich reaction of 3-[4-substituted phenylamino]-2-cyclohexenones and their 5,5-dimethyl derivatives, respectively. Some of the new compounds were tested for their hypotensive activity in normotensive urethane-anesthetized rats in comparison with prazosin. A number of the tested compounds, notably 11, 13, 15, 19, 30 and 34 showed a significant hypotensive activity at i.p. doses of 2.5 and /or 5 mg/kg. The effects of various substitutes at 1 and /or 3 positions of the quinazoline skeleton on the activity were investigated. Compound 34 at i.p. dose of 2.5 mg/kg and 11, 13, 19 and 30 at 5 mg/kg showed alpha-adrenoceptor blocking activity in adrenaline-induced hypertension in anesthetized rats and their order of potency after 30 minutes of injection was 34 > prazosin > 11 > 13 > 30 > 19

Comparative study of cardiac safety profiles of loratadine and astemizole in rats

The second [non-sedating] generation antihistamines; terfenadine and astemizole have been reported to produce QTc prolongation and ventricular arrhythmias. With the withdrawal of terfenadine and the warnings for astemizole recommended by U.S.FDA, loratadine becomes one of the currently widely available non-sedating antihistamines. We examined and compared the effects of loratadine and astemizole on the electrocardiographic QT c interval and heart rate in adult albino rats.Two groups, each 6 anaesthetised adult albino rats; loratadine, and astemizole-treated groups were used. Each drug was given in 4 doses about 0.1, 1, 5 and 10 times its antihistaminic ED[50] in rats, with 30-minutes dosing interval. The heart rate and QT c interval [mean values over the dosing interval] were the electrocardiographic parameters measured. Loratadine doses about 0.1, 1 and 5 times the antihistaminic ED[50] produced insignificant changes in the HR and QTc interval, while the loratadine dose about 10 times the ED[50] produced significant minimal increases in the HR and QT c interval versus the control in rats. Astemizole doses about 0.1 and 1 times its ED[50] produced insignificant changes in the HR, while astemizole doses about 5 and 10 times its EDSO produced significant moderate decrease [opposite to loratadine effect] in the HR. All astemizole doses about 0.1, 1, 5 and 10 times its ED[50] produced significant moderate prolongations in the QT c interval versus the control which were much greater than loratadine effect with its dose 10 times the ED[50]. Loratadine has no or little effects on the HR and QTc interval with doses up to 10 times the ED[50] and is considered to have much better cardiac safety profile in comparison to astemizole doses from 0.1 up to 10 times its ED[50] which is cardiotoxic based on the greater QTc interval prolongations