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Research Interests Our lab is interested in the design, synthesis and electrophysiological screening of potent and selective small molecule ion channel modulators with potential therapeutic applications. Specifically the K+ channels are the main focus of our research. These channels maintain the resting membrane potential of the cell, regulate cell volume in non-excitable cells and fine tune the action potential firing frequency of excitable cells such as cardiac myocytes and neurons. The voltage-gated K+ channels are being validated as important targets for treating autoimmune diseases, neurological and metabolic disorders. For example 5-(4-phenoxybutoxy)psoralen (PAP-1), the most potent blocker of Kv1.3, was developed by our group and is being validated as a therapeutic for treating diseases such as psoriasis, type I diabetes and multiple sclerosis.
Positive modulators of the voltage-independent calcium-activated K+ channels are being studied for the treatment diseases such as stress-induced hypertension, bipolar disorder, ataxia, epilepsy and possibly schizophrenia. Derivatives of 2-aminobenzothiazole, such as Naphtho[1,2-a]thiazol-2-ylamine (SKA-31) decreases stress-induced hypertension in animal models. 2-Amino-5,6-cyclopentenobenzothiazole (SKA-29) and 2-Amino-6-methoxybenzothiazole (SKA-2) has been shown to protect the animal from chemical and electric shock-induced epilepsy.
Many heterocyclic compounds with isolated or fused ring systems exhibit diverse pharmacological activity when properly decorated with substituents which modify the electron density in the pharmacophore. Molecular weight and lipophilicity are the other important considerations for successful design. Another strategy for successful modulator design is to use the Selective Optimization of Side Activity (SOSA) into main activity approach
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Selected Publications "Pharmacokinetics, toxicity and functional studies of the selective Kv1.3 channel blocker PAP-1 in the non-human primate rhesus macaque," Pereira, L.E., Villinger, F., Wulff, H., Sankaranarayanan, A., Raman, G., Ansari, A.A Experimental Biology and Medicine, 2007, 232, 1338-1354. "Modulators of Small- and Intermediate-Conductance Calcium-activated Potassium Channels and their Therapeutic Indications," Wulff, H., Kolski-Andreaco, A., Sankaranarayanan, A., Sabatier, J.M., Shakkottai, V., . Current Medicinal Chemistry, 2007, 14, 1437-1457. "Targeting Effector Memory T cells with the small molecule Kv1.3 blocker, PAP-1, suppresses Allergic Contact Dermatitis," Azam, P., Sankaranarayanan, A., Homerick, D., Griffey, S., Wulff, H., . J Invest Dermatol. 2007, 127(6), 1419-29 "Kv1.3 channels as a therapeutic target for T cell-mediated autoimmune diseases," Beeton, C., Wulff, H., Standifer, N.E., Azam, P., Mullen, K.M., Pennington, M.W., Kolski-Andreaco, A., Wei, E., Grino, A., Counts, D.R., Wang, P.H., LeeHealey, C.J., Andrews, B.S., Sankaranarayanan, A., Homerick, D., Roeck, W.W., Tehranzadeh, J., Stanhope, K.L., Zimin, P., Havel, P.J., Griffey, S., Knaus, H.G., Nepom, G.T., Gutman, G.A., Calabresi, P.A., and Chandy., K.G., PNAS 2006, 103, 17414-17419. "Process Development of the Synthesis of 3,4,5-Trimethoxytoluene," Sankaranarayanan, A.*; Chandalia, S.B. (*Contributing Primary and Communicating Author), Organic Process Research & Development 2006, 10, 487-492. Most Accessed paper of OPRD in 2006. "Engineering for biosynthesis of ectoine (2-methyl 4-carboxy tetrahydro pyrimidine) in tobacco chloroplasts leads to accumulation of ectoine and enhanced salinity tolerance," Rai, M., Pal, M., Sumesh, K.V., Jain, V., Sankaranarayanan, A., . Plant Science 2006, 170(2), 291-306. "Design of PAP-1 a selective small molecule Kv1.3 blocker for the suppression of effector memory T cells in autoimmune diseases," Schmitz, A.*,Sankaranarayanan, A.*, (*joint first authors), Azam, P., Schmidt-Lassen, K., Homerick, D., Hänsel, W., Wulff, H., Molecular Pharmacology 2005, 68(5), 1254-1270. "K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom," Mouhat, S., Visan, V., Sankaranarayanan, A., Wulff, H., Andreotti, N., Grissmer, S., Darbon, H., De Waard, M., Sabatier, J.M., Biochemical Journal 2005, 385(1), 95-104. "Oxidative Bromination in a Liquid-Liquid Two phase System to synthesize Organic intermediates: 2-Bromophenol, 2,6-Dibromophenol, 2-Bromo-4-methylphenol," Mukhopadhyay, S., Sankaranarayanan, A., Chandalia, S.B., . Organic Process Research & Development 1999, 3(6), 451-454.
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