4-Chloro-7-Trifluoromethyl-10<i>H-</i> Benzo[4,5]furo[3,2-<i>b</i>]Indole-1-Carboxylic Acid (TBIC), a Putative BK_Ca Channel Opener with Uterine Relaxant Activities

Abstract

In the present study, we examined the uterine relaxant activity of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), a putative opener of the large conductance Ca²⁺-activated K⁺ (BK_Ca) channel. TBIC concentration-dependently inhibited spontaneous uterine contractions (EC₅₀ = 4.63 µmol/l; E_max = 94.85 ± 1.85%; 100 µmol/l, n = 6). It also reduced contractions induced by oxytocin (EC₅₀ = 4.10 µmol/l; E_max = 84.3 ± 3.83%; 100 µmol/l, n = 6), prostaglandin F₂_α (EC₅₀ = 2.14 µmol/l; E_max = 73.70 ± 5.21%; 100 µmol/l, n = 6) and acetylcholine (EC₅₀ = 4.37 µmol/l; E_max = 83.67 ± 4.82; 100 µmol/l, n = 6). TBIC decreased KCl (20 mmol/l) -induced contractions (EC₅₀ = 3.04 µmol/l; E_max = 94.0 ± 3.12%; 100 µmol/l, n = 6) indicating its K⁺ channel opening activity. BK_Ca channel blockers penitrem A (100 nmol/l) and tetraethylammonium chloride (1 mmol/l) attenuated the inhibitory activities of TBIC (p < 0.001) but not other K⁺ channel blockers such as barium chloride and glibenclamide (K_IR and K_ATP channel blockers, respectively). These results demonstrate the uterine relaxant effects of TBIC in a mechanism of action largely referable to the potentiation of the BK_Ca channels. We have provided evidence for the potential use of TBIC as a tocolytic agent and support for the utility of BK_Ca channel openers in pathophysiologic conditions involving smooth muscle hyperactivity.

On Benzofuroindole Analogues as Smooth Muscle Relaxants

“…Nevertheless, the effects of compound 22 were all consistent with the activation of BK Ca channels, as evidenced by the counter effects of BK Ca channel blockers iberiotoxin or penitrem A [26, 43, 44] on the relaxative effects of compound 22 in high K + - (20 mM KCl-) induced contractions (Table 1). Other ion channels or contractile machineries may also be at play considering the effects of compound 22 in high-K + - (60–80 mM KCl-) induced contractions [26, 43, 44, 48, 49]. Taken together, these findings indicate that in addition to bladder-relaxant activities, compound 22 also influences intestinal and uterine contractions.…”

“…As not much is known about the effects of benzofuroindole compounds in other tissues, an ongoing effort has been made to investigate this matter. Compound 22 also displayed potent inhibition of both spontaneous and agonist-induced contractions of the ileum [43] and uterus [44]. EC 50 values of the relaxant effects of compound 22 are shown in Table 1.…”

“…In bladder and ileum strips, however, compound 22 was not as potent as atropine, an antimuscarinic drug, in inhibiting ACh-induced contractions [26, 43]. In the uterus, although compound 22 relaxed oxytocin, prostaglandin F2 α , and ACh-induced contractions, its effects were not as potent as those of standard tocolytics (note, however, the similarity in the degree of potency between diclofenac and compound 22 in inhibiting PGF2 α -induced contractions) [44]. Nevertheless, the effects of compound 22 were all consistent with the activation of BK Ca channels, as evidenced by the counter effects of BK Ca channel blockers iberiotoxin or penitrem A [26, 43, 44] on the relaxative effects of compound 22 in high K + - (20 mM KCl-) induced contractions (Table 1).…”

“…In the uterus, although compound 22 relaxed oxytocin, prostaglandin F2 α , and ACh-induced contractions, its effects were not as potent as those of standard tocolytics (note, however, the similarity in the degree of potency between diclofenac and compound 22 in inhibiting PGF2 α -induced contractions) [44]. Nevertheless, the effects of compound 22 were all consistent with the activation of BK Ca channels, as evidenced by the counter effects of BK Ca channel blockers iberiotoxin or penitrem A [26, 43, 44] on the relaxative effects of compound 22 in high K + - (20 mM KCl-) induced contractions (Table 1). Other ion channels or contractile machineries may also be at play considering the effects of compound 22 in high-K + - (60–80 mM KCl-) induced contractions [26, 43, 44, 48, 49].…”

Urinary Bladder-Relaxant Effect of Kurarinone Depending on Potentiation of Large-Conductance Ca2+-Activated K+ Channels

“…Thus, it is possible to induce the relaxation of UBSM by chemically activating the endogenous BK Ca channel. In fact, several activator compounds for BK Ca channels have been reported for their relaxation effect on the urinary bladder (dela Pena et al, 2009;Layne et al, 2010;Ahn et al, 2011;Park et al, 2014), further indicating the potential of this channel as a treatment target for OAB syndrome. However, the potency and specificity of BK Ca channel activators remain a problem for their clinical usage (Nardi and Olesen, 2006;Bentzen et al, 2014).…”