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Chemical Compound Review

Tocris-1355     3-cyano-2-(2-methylbutan-2- yl)-1-pyridin-3...

Synonyms: CHEMBL11458, AG-G-17630, CHEBI:109027, CCG-101122, LS-73457, ...
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Disease relevance of Tocris-1355

  • P-1075 induced a cardiac contracture (left ventricular end diastolic pressure increased from 6 to 60 mmHg) and a cardiac arrest after an infusion of approximately 9 min [1].
  • In subsequent studies, hindlimb remote IPC or intravenous injection of the sarcolemmal K(ATP) (sK(ATP)) channel opener P-1075 (2 microg/kg) at 24 h before 4 h of sustained ischemia (i.e., late preconditioning) reduced muscle infarction from 43 +/- 4% (ischemic control) to 24 +/- 2 and 19 +/- 3%, respectively (P < 0.05, n = 8) [2].
  • Treatment with 75 nM P-1075 both before and after ischemia did not add to the protective effects observed after preischemic treatment [3].
  • We investigated consequences of cardiac arrest on sarcolemmal and mitochondrial effects of ATP-sensitive potassium channel (KATP) opener, P-1075, in Langendorff-perfused rat hearts [4].

High impact information on Tocris-1355


Chemical compound and disease context of Tocris-1355

  • HMR 1098 also prevented cardiac arrest and mitochondrial uncoupling induced by P-1075, such as (a) depletion of phosphocreatine and ATP by 40%, (b) two-fold decrease in venous oxygen, and (c) reduction of cytochrome c oxidase (demonstrated by an increase in 603 nm optical absorbance) [9].

Biological context of Tocris-1355

  • A 20 min infusion of 5 microm P-1075 depleted phosphocreatine and ATP by approximately 40%, concomitantly with a two-fold increase in inorganic phosphate, while oxygen consumption by the hearts increased by 50% [1].
  • P-1075, the most potent compound of the series (EC50 = 3.7 x 10(-8) M), reduced the APD of Purkinje fibers by a maximum of 91 +/- 2% at 10(-6) M with no change in the maximum rate of rise (Vmax) or conduction time of the action potential [10].
  • Lack of P-1075 mitochondrial effects in depolarized hearts was not due to changes in phosphorylation potential, because 2,4-dintrophenol (10 microM) reversed the [PCr]/[Cr] increase and Pi decrease, characteristic of KCl-arrest, but did not restore uncoupling [4].
  • This novel and highly plausible cellular mechanism for pmKATP-mediated cardioprotection may have direct clinical relevance as evidenced by the following findings: a hypokalemic polarizing cardioplegia solution supplemented with the pmKATP opener P-1075 improved Ca2+ homeostasis and recovery of function compared with hyperkalemic depolarizing St [11].

Anatomical context of Tocris-1355


Associations of Tocris-1355 with other chemical compounds

  • None of the KATP openers tested, cromakalim (300 microM), P-1075 (10 microM) and pinacidil (100 microM), affected twitch force during normoxia [12].
  • Activation of sarcolemmal KATP by P-1075 (5 microM) and a mitochondrial uncoupler 2,4-dinitrophenol (DNP) (50 microM) stimulated Rb+ efflux from the hearts by 130% and 60%, respectively [9].

Gene context of Tocris-1355

  • KO ventricular cells exhibited no response to KCOs, but gene transfer of Kir6.2 into neonatal ventricular cells rescued the electrophysiological response to P-1075 [13].
  • We investigated effects of blockade of cardiac ATP-sensitive potassium channels (KATP) with a novel cardioselective sulfonylthiourea, HMR 1098, on metabolic uncoupling caused by a potent KATP opener, P-1075, in Langendorff-perfused rat hearts [9].

Analytical, diagnostic and therapeutic context of Tocris-1355


  1. Effects of K(ATP) channel openers, P-1075, pinacidil, and diazoxide, on energetics and contractile function in isolated rat hearts. Jilkina, O., Kuzio, B., Grover, G.J., Kupriyanov, V.V. J. Mol. Cell. Cardiol. (2002) [Pubmed]
  2. Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: efficacy and mechanism. Moses, M.A., Addison, P.D., Neligan, P.C., Ashrafpour, H., Huang, N., McAllister, S.E., Lipa, J.E., Forrest, C.R., Pang, C.Y. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2005) [Pubmed]
  3. Cardioprotective effects of the cyanoguanidine potassium channel opener P-1075. Sargent, C.A., Sleph, P.G., Dzwonczyk, S., Normandin, D., Antonaccio, M.J., Grover, G.J. J. Cardiovasc. Pharmacol. (1993) [Pubmed]
  4. Sarcolemmal and mitochondrial effects of a KATP opener, P-1075, in "polarized" and "depolarized" Langendorff-perfused rat hearts. Jilkina, O., Kuzio, B., Grover, G.J., Folmes, C.D., Kong, H.J., Kupriyanov, V.V. Biochim. Biophys. Acta (2003) [Pubmed]
  5. Pharmacological comparison of native mitochondrial K(ATP) channels with molecularly defined surface K(ATP) channels. Liu, Y., Ren, G., O'Rourke, B., Marbán, E., Seharaseyon, J. Mol. Pharmacol. (2001) [Pubmed]
  6. Activation of mitochondrial ATP-sensitive potassium channels increases cell viability against rotenone-induced cell death. Tai, K.K., McCrossan, Z.A., Abbott, G.W. J. Neurochem. (2003) [Pubmed]
  7. Potassium channel conductance as a control mechanism in hair follicles. Buhl, A.E., Conrad, S.J., Waldon, D.J., Brunden, M.N. J. Invest. Dermatol. (1993) [Pubmed]
  8. Pharmacological activation of plasma-membrane KATP channels reduces reoxygenation-induced Ca(2+) overload in cardiac myocytes via modulation of the diastolic membrane potential. Baczkó, I., Giles, W.R., Light, P.E. Br. J. Pharmacol. (2004) [Pubmed]
  9. Cardioselective sulfonylthiourea HMR 1098 blocks mitochondrial uncoupling induced by a KATP channel opener, P-1075, in beating rat hearts. Jilkina, O., Kuzio, B., Grover, G.J., Kupriyanov, V.V. Biochim. Biophys. Acta (2003) [Pubmed]
  10. Cardiac electrophysiological effects of pinacidil and related pyridylcyanoguanidines: relationship to antihypertensive activity. Smallwood, J.K., Steinberg, M.I. J. Cardiovasc. Pharmacol. (1988) [Pubmed]
  11. Plasma membrane KATP channel-mediated cardioprotection involves posthypoxic reductions in calcium overload and contractile dysfunction: mechanistic insights into cardioplegia. Baczkó, I., Jones, L., McGuigan, C.F., Manning Fox, J.E., Gandhi, M., Giles, W.R., Clanachan, A.S., Light, P.E. FASEB J. (2005) [Pubmed]
  12. ATP-sensitive potassium channels and skeletal muscle function in vitro. Weselcouch, E.O., Sargent, C., Wilde, M.W., Smith, M.A. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  13. Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Suzuki, M., Li, R.A., Miki, T., Uemura, H., Sakamoto, N., Ohmoto-Sekine, Y., Tamagawa, M., Ogura, T., Seino, S., Marbán, E., Nakaya, H. Circ. Res. (2001) [Pubmed]
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