A new centrally acting antihypertensive (ICI 106270) which separates antihypertensive effects from sedation.
1. 6-(2-Chloro-6-fluorophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[1,2-a]-imidazole hydrobromide (ICI 106270) has been developed with the objective of achieving satisfactory blood pressure (BP) reduction while minimising the side-effects seen with clonidine. 2. In the pentobarbitone sodium anaesthetised rat the dose of ICI 106270 to lower BP by 20 mmHg (ED20) was 5.45 micrograms/kg i.v. (ED20 clonidine 1.18 micrograms/kg i.v.). In conscious spontaneously hypertensive rats 10 mg/kg orally of ICI 106270 lowered BP by 70 +/- 12.2 mmHg. A similar fall in BP of 67 +/- 6.5 mmHg was seen with 1 mg/kg of clonidine orally. 3. In conscious renal-hypertensive dogs ICI 106270 is 2--3 times less potent than clonidine when dosed either p.o. or i.v. but was equipotent with clonidine at lowering BP when administered into a lateral cerebral ventricle. 4. Clonidine (250--750 micrograms/kg) administered i.p. in rats caused a marked potentiation of anaesthesia induced by pentobarbitone. ICI 106270 similarly administered in the same doses was without effect. 5. In a test for locomotor activity the ED50 (dose to reduce locomotor activity by 50%) was 15.3 micrograms/kg i.v. for clonidine and 237.5 micrograms/kg i.v. for ICI 106270. On oral administration the ED50 for clonidine was 26 micrograms/kg and for ICI 106270 it was 2.14 mg/kg. 6. In the chloralose anaesthetised cat pre- and post-ganglionic sympathetic efferent nerve activity was reduced by ICI 106270 in doses which also reduced BP. 7. The hypotensive effect of i.v. ICI 106270 in anaesthetised rats was antagonised by the alpha-adrenoceptor antagonists yohimbine and piperoxan. 8. These results indicate that ICI 106270 is a potent antihypertensive with a similar mechanism of action to clonidine although it is relatively less sedative. It is an alpha-stimulant and its site of action is probably within the CNS.
D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010424:Pentobarbital; D051381:Rats; D012890:Sleep / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects
D000959:Antihypertensive Agents; D007093:Imidazoles; C032860:ICI 106270; D010424:Pentobarbital; D003000:Clonidine