, Volume 33, Supplement 2, pp 67–74 | Cite as

Cyclandelate as a Calcium Modulating Agent in Rat Cerebral Cortex

  • A. Bast
  • R. Leurs
  • H. Timmerman
Section 1: Pharmacological Studies: Modes and Mechanisms of Action


Cyclandelate is clinically effective in a variety of cerebrovascular indications, but its precise mode of action is unclear. Hence, this study investigated the interaction of cyclandelate, cyclandelate alcohol and cyclandelate acid with the binding sites for radioactively labelled 3H- nitrendipine, a Ca++entry blocker of the 1,4- dihydropyridine type, on rat cerebral cortex membranes. Cyclandelate showed a dissociation constant (Kd) of 7.1 ± 1.4 × 10− 5 mol/L (35% inhibition of 3H- nitrendipine binding at 2 × 10− 4 mol/L cyclandelate), cyclandelate alcohol had a Kd value of 1.7 ± 0.1 × 10− 4 mol/L (maximal 70% inhibition of 3H- nitrendipine binding) whereas cyclandelate acid was inactive. For comparison, nifedipine (Kd of 2.6 ± 0.3 × 10− 9 mol/L inhibition of 68% of 3H- nitrendipine binding), d- cis diltiazem (Kd of 1.1 ± 0.1 × 10−7mol/L enhancement of 39% of 3H nitrendipine binding) and ± -verapamil [Kd values of 1.4 ± 0.4 × 70−7mol/L (38% inhibition) and 5.3 ± 1.7 × 10− 4 mol/L (62% inhibition)] were used.

Thus, cyclandelate may exert its clinical activity in cerebral ischaemia or hypoxia at least in part through a calcium modulatory effect.


Verapamil Nifedipine Diltiazem Nitrendipine Entry Blocker 


En clinique, le cyclandélate est indiqué dans le traitement de nombreux troubles vasculaires cérébraux. Son mécanisme d’action précis n’est cependant pas clair. En conséquence, la présente étude a été consacrée à la recherche des éventuelles interactions du cyclandélate, du cyclandélate alcool et du cyclandélate acide avec les sites de liaison de la nitrendipine tritiée, un bloqueur de l’entrée de Ca2+ du type de la 1,4-dihydropyridine, dans les membranes du cortex cérébral du rat. La constante de dissociation (Kd) du cyclandélate a été de 7,1 ± 1,4 × 10−5 mol/l (35% d’inhibition de la liaison de la 3H-nitrendipine pour une concentration de cyclandélate de 2. 10−4 mol/l). Le Kd du cyclandélate alcool a été de 1,7 ± 0,1 × 10−4 mol/l, avec une inhibition maximale de 70% de la liaison de la 3H-nitrendipine, alors que le cyclandélate acide s’est montré inactif. Pour comparer ces valeurs à celles de produits connus, on a utilisé la nifédipine (Kd=2,6 ± 0,3 × 10−9 mol/l; inhibition de la liaison de la 3H-nitrendipine: 68%), le d-cis diltiazem (Kd=1,1 ± 0,1 x 10−7 mol/l; renforcement de la liaison de la 3H-nitrendipine: 39%) et le vérapamil racémique (Kd=1,4 ± 0,4 × 10−7 molli, inhibition: 38% et Kd=5,3 ± 1,7 × 10−4mol/l, inhibition: 62% pour les formes dextrogyre et lévogyre).

En conséquence, il semble que l’activité clinique du cyclandélate sur l’ischémie cérébrale et l’hypoxie passe, au moins en partie, par un blocage de l’entrée intra-cellulaire des ions calcium.


Il ciclandelato è clinicamente efficace in varie indicazioni cerebrovascolari, ma il suopreciso meccanismo d’azione non risulta chiaro. Questa ricerca ha esaminato, sulle membrane della corteccia cerebrale del ratto, I’interazione del ciclandelato, delValcool ciclandelico e dell’acido ciclandelico con i siti di legame della 3H-nitrendipina, radioattivamente marcata, un bloccante dell’ingresso del Ca2+ del tipo della 1,4-diidropiridina. Il ciclandelato ha dimostrato una costante di dissociazione (Kd × 7,1 ± 1,4 × 10−5 mol/l (35% di inibizione delia 3H-nitrendipina che si lega al ciclandelato a 2 × 10−4 mol/l). L’alcool ciclandelico aveva un valore della Kd di 1,7 ±0,1 × 10−4 mol/l (inibizione massima al 70% del legame con la 3H-nitrendipina) mentre l’acido ciclandelico era inattivo. Per il confronto furono impiegate lanifedipina (Kd2,6 ± 0,3 × 10−9mol/l, 68% di inibizione dellagame con la 3H-nitrendipina), il d-cisdiltiazem (Kd 1,1 ±0,1 × 10-7 mol/l, rafforzando del 39% il legame con la 3H-nitrendipina) e i valori ± del verapamil (Kd 1,4 ± 0,4 × 10−7 mol/l (38% di inibizione) e5,3 ±1,7 × 10−4 mol/l (62% di inibizione).

Il ciclandelato può esercitare la sua attività clinica nell’ischemia cerebrale o nell’ipossia almeno in parte tramite un effetto bloccante l’ingresso del calcio.


Cyclandelaat is klinisch effectief bij een hele reeks cerebrovasculaire indicaties, maar de precieze werkingsrvijze van de stof is nog onduidelijk. Daarom werd in deze Studie de interactie nagegaan tussen cyclandelaat, cyclandelaatalcohol en cyclandelaatzuur en de bindingsplaatsen voor radioactief gemerkt 3H-nitrendipine, een Ca2+-entry blocker van het 1,4-dihydropyritinetype, op de hersenschorsmembranen van de rat. Cyclandelaat vertoonde een dissociatieconstante (Kd) van 7,1 ± 1,4 × 10−5 mol/l (35 % inhibitie van de 3H-nitrendi-pinebinding bij 2 × 10−4 molli cyclandelaat). Cyclandelaatalcohol had een Kd-waarde van 1,7 ± 0,1 × 10−4 mol/l (maximaal 70% inhibitie van de 3H-nitrendipinebinding), terwijl cyclandelaatzuur inactief was. Ter vergelijking namen we nifedipine (met een Kd-waarde van 2,6 ± 0,3 × 10−9 molli en een inhibitie van 68% van de 3H-nitrendipinebinding), d-cis diltiazem (Kd-waarde van 1,1 ± 0,1 × 10−7 mol/l en een verhoging met 39% van de 3H-nitredipinebinding) en ± -verapamil (Kd-waarden van 1,4 ± 0,4 × 10−7 mol/l (38% inhibitie) en 5,3 ± 1,7 × 10−4mol/l (62% inhibitie).

De klinische activiteit van cyclandelaat bij cerebrale ischemie of hypoxie kan bijgevolg ten minste gedeeltelijk toegeschreven worden aan zijn calciummodulerende effekt.


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Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • A. Bast
    • 1
  • R. Leurs
    • 1
  • H. Timmerman
    • 1
  1. 1.Department of Pharmacochemistry, Subfaculty of ChemistryVrije UniversiteitAmsterdamThe Netherlands

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