(S)-emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders. 2nd communication: brain penetration, cerebral vascular and metabolic effects.
The cerebral availability of the phenylalkylamine calcium antagonist (S)-emopamil ((2S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitril e hydrochloride), was investigated in the anesthetized rat by computing the quotient of brain activity and integrated plasma activity 75 min after intraperitoneal injection of the 14C-labeled substance. The relative cerebral concentration defined in this way amounted to 2.05 for emopamil, 0.11 for verapamil and 0.03 ml/g for gallopamil, corresponding to a ratio of 70:4:1. The cerebral uptake of the same substances during a single capillary passage following intracarotid injection was determined by using tritiated water as an internal standard. Relative to the water the following brain uptake indices were obtained: (S)-emopamil 110.3, gallopamil 45.3 and verapamil 40.6%. According to these figures, emopamil is clearly superior to verapamil and gallopamil both with regard to cerebral availability and blood-brain barrier permeability. The effect of emopamil enantiomers on local cerebral blood flow was studied autoradiographically in the artificially ventilated rat anesthetized with nitrous oxide. The test substances were infused intravenously over 30 min, the determination of local cerebral blood flow being carried out 10 min after the end of the infusion. The numerical evaluation included 40 brain structures. In the investigated regions the infusion of 3 and 6 mg/kg (S)-emopamil led to an average blood flow increase of 24 and 52%, respectively. In the latter experimental group the values for the 22 cerebral structures showing a statistically significant effect were between 128 and 208% of control. In contrast, the application of 6 mg/kg (R)-emopamil did not lead to a significant change in blood flow in any of the areas.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Neuropsychopharmacology, Ludwigshafen/Rhein Fed. Rep. of Germany.
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D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D014700:Verapamil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D002121:Calcium Channel Blockers; D012702:Serotonin Antagonists; D014700:Verapamil; D005947:Glucose; C052752:emopamil