Vasodilator and angioprotective activity of 1-ethyl-1-hydroxyalkyl-octahydroindolo[2,3a]quinolizine derivates.
The blood flow enhancing activity of the homologue series of "trans" racemic 1-ethyl-1-hydroxyalkyl-1,2,3,4,6,7,12,12b-octahydroindolo[2, 3a]quinolizine (1) was studied in anesthetized dogs. It was found that the femoral vasodilator activity is the strongest for 1b, and decreases if the carbon chain is shortened (1a) or lengthened (1c). Also, a breakdown of vasodilation was observed with the racemic "cis" derivative (2). After resolution of 1b the optically active compound 3 retained the dilator capacity while 4 isomer lost it. Hence 3 (RHG-2981, vintoperol, CAS 106498-99-1) was selected for detailed pharmacological study. Dose-response studies performed in anesthetized dogs showed that vintoperol 0.03 mg/kg (i.v.) was more potent as peripheral vasodilator than buflomedil or pentoxifylline at doses ranging from 1 to 15 mg/kg. Similar results were observed during a 4-week cross-over test of maximal running distance of femoral ligated mice. The running performance, as measured by the rotating drum, showed a linear increase in the untreated control group (UCG) as a consequence of every day testing (= intensive endurance training). After bilateral femoral occlusion the maximal running distance of the mice fell off, and despite daily training it stagnated. If 0.3 or 1 mg/kg/d vintoperol or 10 mg/kg/d pentoxifylline was administered orally 4 days after the bilateral femoral occlusion, the maximal running distance increased. In the case of 1.0 mg/kg of vintoperol applied daily, the rate of enhancement approached, or even overtook, that of the UCG. 0.3 mg/kg/d of vintoperol showed less activity, however, this result is still about twice better than the effect of 10 mg/kg/d pentoxifylline.
Pharmacological Research Centre, Chemical Works of Gedeon Richter Ltd., Budapest, Hungary.
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Szombathelyi
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Kárpáti
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Kalaus
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L
Szabó
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Szántay
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006331:Heart Diseases / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology; D010805:Physical Conditioning, Animal; D011807:Quinolizines / Q000494:pharmacology* / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D007211:Indoles; D011807:Quinolizines; D014665:Vasodilator Agents; C066359:vintoperol; D010431:Pentoxifylline