IAA-94 (Synonyms: R(+)-IAA 94)

IAA-94 (Indanyloxyacetic acid-94) is an intracellular chloride channel blocker ^[1]. IAA-94 inhibited CLIC-1-dependent chloride permeability with an apparent IC50 of 8.6 µM ^[2]. IAA-94 depressed the K+-induced force with an IC50 of 17.0 ± 1.2 µM ^[3].

In cells treated with IAA-94 (30 µM) with respect to control, the amount of intracellular Aβ1-42 phagocytosis was remarkably increased after 24 hr of incubation ^[4]. Inhibition of Cl- channels with pan-chloride channel blocker IAA-94 (50 µM) abolished the protection induced by 200 nM CsA pre-treatment in cardiomyocytes ^[5]. The anion channel blocker IAA-94 (200 µM) significantly blocked glutamate and taurine release against Astrocytes in hypotonic solution ^[6].

IAA-94 was shown to abrogate cardioprotection mediated by IPC and cyclosporin A (CsA) ^[7]. Adult male rat hearts were subjected to the left coronary artery occlusion for 45min followed by 3h of reperfusion. A single intravenous bolus of phosphate buffered saline (PBS) (control) or IAA-94 (20mg/kg body weight) was administered 5min before reperfusion. The infarct size (IS) was significantly higher in the IAA-94-treated group compared to control; the ratio of IS to area at risk was 58.1±7% in IAA-94 vs. 33.5±6% in control in this rat model ^[1].

References:
[1]. Ponnalagu D, Hussain A T, Thanawala R, et al. Chloride channel blocker IAA-94 increases myocardial infarction by reducing calcium retention capacity of the cardiac mitochondria[J]. Life sciences, 2019, 235: 116841.
[2]. Tulk B M, Schlesinger P H, Kapadia S A, et al. CLIC-1 functions as a chloride channel when expressed and purified from bacteria[J]. Journal of Biological Chemistry, 2000, 275(35): 26986-26993.
[3]. Doughty J M, Miller A L, Langton P D. Non‐specificity of chloride channel blockers in rat cerebral arteries: block of the L‐type calcium channel[J]. The Journal of physiology, 1998, 507(2): 433-439.
[4]. Paradisi S, Matteucci A, Fabrizi C, et al. Blockade of chloride intracellular ion channel 1 stimulates Aβ phagocytosis[J]. Journal of neuroscience research, 2008, 86(11): 2488-2498.
[5]. Diaz R J, Fernandes K, Lytvyn Y, et al. Enhanced cell-volume regulation in cyclosporin A cardioprotection[J]. Cardiovascular research, 2013, 98(3): 411-419.
[6]. Ye Z C, Oberheim N, Kettenmann H, et al. Pharmacological “cross‐inhibition” of connexin hemichannels and swelling activated anion channels[J]. Glia, 2009, 57(3): 258-269.
[7]. Diaz R J, Losito V A, Mao G D, et al. Chloride channel inhibition blocks the protection of ischemic preconditioning and hypo-osmotic stress in rabbit ventricular myocardium[J]. Circulation research, 1999, 84(7): 763-775.