(S)-emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders. 1st communication: pharmacological profile.
(S)-Emopamil ((2S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitril e hydrochloride) is a novel compound of the phenylalkylamine group of calcium antagonists. (S)-Emopamil was tested in comparison to verapamil and gallopamil for calcium and serotonin antagonism and for cerebroprotective activity in acute hypoxia/ischemia. In receptor binding studies with (S)-3H-devapamil, (S)-emopamil exhibited distinct affinity to the verapamil binding site of the calcium channel. In rat cerebrocortical membranes, its affinity (Ki = 38 nmol/l) equalled that of verapamil and gallopamil (Ki = 49 and 27 nmol/l, respectively), whereas it was somewhat weaker in guinea pig skeletal muscle membranes. Comparing (S)-emopamil to its (R)-enantiomer, there was no clear stereoselectivity. Additionally, (S)-emopamil showed very high affinity to the cerebral serotonin S2 receptor; its Ki value (4.4 nmol/l) for 3H-ketanserin displacement being substantially lower than that of verapamil and gallopamil (Ki = 177 and 242 nmol/l, respectively). This feature is clearly stereoselective; (S)-emopamil's affinity was distinctly higher than that of the (R)-enantiomer (Ki = 58 nmol/l). The functional significance of (S)-emopamil's receptor affinity was tested in rat aortic strips. (S)-Emopamil's serotonin antagonistic efficacy (EC50 = 4.5 nmol/l) was an order of magnitude higher than that of verapamil and gallopamil. (S)-Emopamil has a less potent calcium antagonistic effect (EC50 = 270 nmol/l) on the aorta than verapamil and gallopamil (EC50 = 35 and 14 nmol/l, respectively). In isolated electrically driven (1 Hz) left atria of guinea pigs, (S)-emopamil inhibited contractile force at a much higher concentration (EC50 = 29 mumol/l) than verapamil and gallopamil (EC50 = 1.1 and 0.19 mumol/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Hofmann
H P
HP
Research and Development, Kenoll AG, Ludwigshafen, Rhein, Federal Rep. of Germany.
Raschack
M
M
Unger
L
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D000818:Animals; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000627:therapeutic use*; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000517:prevention & control; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009132:Muscles / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000378:metabolism / Q000627:therapeutic use*; D014700:Verapamil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
D002121:Calcium Channel Blockers; D012702:Serotonin Antagonists; D007650:Ketanserin; D014700:Verapamil; C052752:emopamil; C055885:devapamil