Selective Inhibition of Calcium Entry Induced by Benzylisoquinolines in Rat Smooth Muscle

Abstract

The mechanism of relaxant activity of six benzylisoquinolines was examined in order to determine the minimal structural requirements that enable these compounds to have either a non-specific action like papaverine or an inhibitory activity on calcium entry via potential-operated channels. All the alkaloids tested totally or partially relaxed KCl-depolarized rat uterus and inhibited oxytocin-induced rhythmic contractions. Only glaucine and laudanosine inhibited K(+)-induced uterine contractions more than oxytocin-induced uterine contractions. In Ca(+)-free medium, sustained contractions induced by oxytocin or vanadate were relaxed by the alkaloids tested except for glaucine and laudanosine indicating no inhibitory effect on intracellular calcium release. Those alkaloids containing an unsaturated heterocyclic ring (papaverine, papaverinol, papaveraldine, N-methylpapaverine and dehydropapaverine) exhibited a more specific activity than those with a tetrahydroisoquinoline ring.

Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, α1‐adrenoceptor and benzothiazepine binding site at the calcium channel

“…This structural feature implies a more specific activity, similar to that of Ca2"-entry blockers (D'Ocon et al, 1989;Anselmi et al, 1992). This selective action showed by benzyltetrahydroisoquinolines implies an inhibition of Ca2"-influx from the extracellular medium without changes in the intracellular distribution of this ion.…”

“…This selective action showed by benzyltetrahydroisoquinolines implies an inhibition of Ca2"-influx from the extracellular medium without changes in the intracellular distribution of this ion. In contrast, the benzylisoquinolines with an unsaturated ring induce a relaxation mediated by both a decrease in the Ca-entry through specific channels and a decrease in the intracellular free Ca2"-levels (Cortes et al, 1990;Anselmi et al, 1992).…”

“…Glaucine, in rat uterus, showed a relaxant 1991). One of these new compounds is glaucine, an aporactivity similar to that of nifedipine (Anselmi et al, 1992), phine that is structurally related to papaverine (Figure 1), but acting by a more specific mechanism related to inhibition of shows a mechanism of uterine smooth muscle relaxant Ca2+-entry through potential operated Ca2+ channels and activity which is different from papaverine. has no effect on Ca2+-release or Ca2+-redistribution from…”

Mechanism of the cardiovascular activity of laudanosine: comparison with papaverine and other benzylisoquinolines

“…The results of our previous work on the structure-activity relationship of benzylisoquinoline alkaloids has made it possible to divide them into two groups, the first one containing those that have an unsaturated heterocyclic ring, like papaverine, and the second one formed by compounds with a tetrahydroisoquinoline ring. The latter group exhibits a more specific activity (Cortes et al, 1990;D'Ocon et al, 1991;Anselmi et al, 1992) and the selectivity implies that these tetrahydroisoquinoline alkaloids, unlike papaverine, act mainly on the Ca2" influx from the extracellular medium without producing changes in the intracellular distribution of this ion. This more specific action on calcium entry, was accompanied by a loss in the activity of these alkaloids as PDEs inhibitors.…”

Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies

“…These antagonists include competitive and noncompetitive antagonists and partial agonists at strychnine insensitive glycine receptors, and antagonists acting at polyamine binding sites. MK-801 (a use-dependent channel blocker or noncompetitive antagonist) and CGP 37849 (a competitive antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants [236, 238, 239]. Furthermore, ketamine is noncompetitive NMDARs antagonist and a derivative of PCP which was found to produce rapid, robust, and persistent antidepressant effects clinically [240, 241].…”