α-Adrenoceptor Interaction of Tetrandrine and Isotetrandrine in the Rat: Functional and Binding Assays

Abstract

The action of 1S,1'S-tetrandrine, a bisbenzyltetrahydroisoquinoline alkaloid, on alpha1-adrenoceptors has been compared with that of its isomer 1R,1'S-isotetrandrine. The work includes binding assays to analyse the affinity of these products for the [3H]prazosin binding site of rat cerebral cortical membranes and functional studies on rat isolated aorta to examine the effects of both alkaloids on intracellular calcium processes related or not to alpha-adrenoceptor activation. A radioligand receptor-binding study showed that both compounds interacted with the alpha1-adrenoceptors displacing [3H]prazosin from the specific binding site. The Ki values (inhibition constants) were 0.69+/-0.12 and 1.6+/-0.4 microM for tetrandrine and isotetrandrine, respectively. The functional studies showed that both alkaloids concentration-dependently inhibited noradrenaline-induced contraction in Ca2+-free solution (IC50 values, i.e. the concentrations needed to induce 50% inhibition, were 252.8 and 174.9 microM for tetrandrine and isotetrandrine, respectively), the spontaneous contractile response elicited by extracellular calcium after depletion of noradrenaline-sensitive intracellular stores (increase in resting tone; IC50 values 11.6 and 19.6 microM for tetrandrine and isotetrandrine, respectively) and the refilling of intracellular Ca2+ stores sensitive to noradrenaline (IC50 values 7.4 and 14.9 microM for tetrandrine and isotetrandrine, respectively). The results show that tetrandrine and isotetrandrine interact with alpha1-adrenoceptors by displacing the [3H]prazosin binding site and that both compounds inhibit mainly the Ca2+-dependent process and have less action on alpha1-adrenoceptors. Tetrandrine is more potent than isotetrandrine.

Simplified Tetrandrine Congeners as Possible Antihypertensive Agents with a Dual Mechanism of Action

“…4,6,7 Although the smooth muscle relaxant and hypotensive action of tetrandrine is attributed to the selective blockade of calcium channels, 5,8,9 its interaction with R 1 -adrenergic receptors, which also modulate calcium channels, may be significant. 10 These data suggest tetrandrine as a lead for the development of antihypertensive drugs with a dual mechanism of action.…”

“…Tetrandrine ( 2 ) is the major BBIQ of “han fangji” ( Stephania tetrandra, Menispermaceae) and is the most characteristic active constituent of this Chinese herbal remedy, which has been used for centuries in the treatment of hypertension . A number of BBIQs have been compared with tetrandrine and in most cases have been found to be less effective as smooth muscle relaxants or L-type calcium channel blockers. − Within this set of BBIQs, higher smooth muscle relaxant potencies have been ascribed to the presence of two biphenyl ether linkages, the (1 S ,1‘ S ) configuration, and extensive N- and O- methylation. ,, Although the smooth muscle relaxant and hypotensive action of tetrandrine is attributed to the selective blockade of calcium channels, ,, its interaction with α 1 -adrenergic receptors, which also modulate calcium channels, may be significant . These data suggest tetrandrine as a lead for the development of antihypertensive drugs with a dual mechanism of action.…”

“…The affinities of all the coclaurine derivatives for α 1 -adrenergic receptors were assessed in binding studies in rat brain cortical homogenates using the subtype nonselective radioligand [ 3 H]prazosin. A subset of these compounds was assayed for affinity for the benzothiazepine modulatory site of the L-type Ca 2+ channel displacing [ 3 H]diltiazem, and eight of them were selected for functional testing as α 1 -adrenergic antagonists or Ca 2+ channel blockers in rat thoracic aorta, contracted with noradrenaline or by depolarization with KCl, respectively . The results were compared with available data for coclaurine itself and for tetrandrine.…”

Pharmacological hypothesis: TPC2 antagonist tetrandrine as a potential therapeutic agent for COVID‐19

“…By contrast, there is evidence to suggest tetrandrine prevents QT prolongation induced by chemotherapeutic agents 36 . However, tetrandrine has been shown in some animal studies to counteract adrenaline‐ and ouabain‐induced arrhythmias (reviewed in 31), and to interact with α 1 adrenoceptors 37,38 . However, other animal experiments have suggested only minimal interaction with α 1 adrenoceptors but antagonism at α 2 adrenoceptors 39 .…”

The Neuroprotective Effect of Isotetrandrine on Parkinson’s Disease via Anti-Inflammation and Antiapoptosis In Vitro and In Vivo

“…It is considered as an analgesic, antimicrobial, immunosuppressive, and antimalarial agent [ 15 ]. It is also known as a cell-permeable PLA2 inhibitor and has also shown to inhibit α 1 adrenoceptor [ 16 , 17 ]. However, the neuroprotective activity of ITD has not been investigated yet.…”