Research Terms
Industries
Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R. (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch. Gen. Psychiat., 63, 630-8. [PMID:16754836]
Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR. (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am. J. Psychiat.165, 1040-1047 [PMID:18381905]
Arias HR, Xing H, MacDougall KM P, Blanton MP, Soti F, Kem WR (2009) Interaction of DMXBA (GTS-21) and its primary metabolite with agonist and allosteric sites on muscle nicotinic acetylcholine receptors. Brit. J. Pharmacol. 157, 320-330. [PMCID:2697798]
Hibbs RE, Sulzenbacher G, Shi J, Talley TT, Kem WR, Marchot P, Taylor P, Bourne Y (2009) Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal α7 nicotinic acetylcholine receptor. EMBO J. 28, 3040-51. [PMCID:2760105]
Papke RL, Kem WR, Soti F, Lopez-Hernandez GY, Horenstein NA (2009) Activation and desensitization of nicotinic alpha7-type acetylcholine receptors by benzylidene anabaseines and nicotine. J. Pharmacol. Exp. Ther. 329, 791-807. [PMCID:2672872]
López-Hernández GY, Thinschmidt JS, Morain P, Trocme-Thibierge C, Kem WR, Soti F, Papke RL. (2009) Positive modulation of alpha7 nAChR responses in rat hippocampal interneurons to full agonists and the alpha7-selective partial agonists, 4OH-GTS-21 and S 24795. Neuropharmacol., 56, 821-30. [PMCID:2775526]
Tregellas JR, Olincy A, Johnson L, Tanabe, Shatti S, Martin LF, Singel D, Du Y, Soti, F, Kem WR, Freedman R (2009) Functional Magnetic Resonance Imaging Effect of an Alpha7 Nicotinic Acetylcholine Receptor Agonist on Schizophrenic Brains. Neuropsychopharmacol. 35(4), 938-42. [PMCID:2834253]
Kem WR, Rocca J, Garraffo HM, Spande TF, Daly JW, Soti F (2009) Synthesis and spectroscopic comparison of the eight methyl-2,3’-bipyridyls and identification of a hoplonemertine alkaloid as 3-methyl-2,3’-bipyridyl. Heterocycles 79, 1025-1041. [DOI 10.39871/COM-08-S(D)80]
Slavov SH, Maksim Radzvilovits M, Susan LeFrancois S, Iva B. Stoyanova-Slavova IB, Soti F, Kem WR, Katritzky AR (2010) A computational study of the binding of 3-(arylidene) anabaseines to two major brain nicotinic acetylcholine receptors and to the acetylcholine binding protein. Eur J Med. Chem. 45, 2433–2446. [PMID:20236734]
Green BT, Lee ST, Panter KE, Welch KD, Cook D, Pfister JA, Kem WR (2010) Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors. Neurotoxicol Teratol. 32(3):383-90. [PMID:20116429]
Shen H, Kihara T, Hongo H, Wu X, Kem WR, Shimohama S, Akaike A, Niidome T, Sugimoto H. (2010) Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. Brit. J. Pharmacol. 161, 127-39. [PMCID:2962822]
Stevens KE, Cornejo B, Adams CE, Zheng L, Yonchek J, Hoffman KL, Christians U, and Kem WR (2010) Continuous administration of a selective α7 nicotinic partial agonist, DMXBA, improves sensory inhibition without causing tachyphylaxis or receptor upregulation in DBA/2 mice. Brain Res. 1352, 140-146. [NIHMS: 224300]
Wu X, Shimohama S, Kem W, Akaike A, Niidome T, Sugimoto H (2010) Neuroprotective effect of donepezil against glutamate toxicity: Involvement of α7 nicotinic acetylcholine receptor stimulation and NMDA receptor internalization. Brit. J. Pharmacol. 161,127-39. [PMCID:2962822]
Rouchaud A, Kem WR (2010) A convenient racemic synthesis of two isomeric tetrahydropyridyl alkaloids: Isoanatabine and anatabine. J. Heterocyclic Chem. 47, 569- 581. [DOI 10.1002/jhet.359]
Tregellas JR, Tanabe J, Rojas DC, Shatti S, Olincy A, Johnson L, Martin LF, Soti F, Kem WR, Leonard S, Freedman R (2011) Effects of an alpha7-nicotinic agonist on default network activitiy in schizophrenia. Biol. Psychiat. 69, 7-11. [PMCID:3005969]
Kalappa BI, Feng L, Kem WR, Gusev AG, Uteshev VV (2011) Mechanisms of facilitation of synaptic glutamate release by nicotinic agonists in the nucleus of the solitary tract. Amer. J. Physiol. Cell Physiol. 301, C347-361. [PMCID:154558]
Suzuki S, Kawamata J, Matsushita T, Matsumura A, Hisahara S, Takata K, Kitamura Y, Kem WR, Shimohama S (2012) 3-[2,4-Dimethoxy)Benzylidene]-anabaseine dihydrochloride prevents 6-hydroxydopamine-induced Parkinsonism neurodegeneration through α7 nicotinic acetylcholine receptor stimulation in rats. J. Neurosci. Res. 91, 462-71 (doi: 10.1002/jnr.23160. Epub 2012 Dec 14).
Isaacson MD, Horenstein NA, Stokes C, Kem WR, Papke RL (2013) Point-to-point ligand-receptor interactions across the subunit interface modulate the induction and stabilization of conformational states of alpha7 nAChR by benzylidene-anabaseines. Biochem. Pharmacol., 85, 817-828. [doi: 10.1016/j.bcp.2013.01.010. Epub 2013 Jan 23]
These compounds enable effective treatment of neurological disorders involving cognitive deficits (including Alzheimer’s and Parkinson’s diseases), depression and drug dependences such as tobacco (nicotine) and betel nut addictions. Neurological diseases including drug addictions are a major health cost to human societies. By 2030, more than 8 million individuals will die annually from illnesses caused by tobacco use, while 600 million individuals remain addicted to some form of betel nut or quid, a psychoactive substance that is carcinogenic. Drugs available to help individuals quit an addictive habit often have undesirable side effects or are ineffective. Researchers at the University of Florida have developed a variety of nicotinic receptor agonists (activators) based on a marine natural product named anabaseine that selectively stimulate only one of a large number of nicotinic receptors found in the mammalian brain; the alpha7 receptor is a major mediator of brain activity associated with learning and memory. Stimulation of this receptor also has anti-inflammatory actions that are thought to be involved in neuroprotective action in neurodegenerative disease animal models. On the other hand, antagonists based on a plant compound, cytisine, are important in treating tobacco and other chemical addictions. Empirical results suggest that when combined, the two types of compounds offer a more effective reduction in nicotine addiction than currently available drugs.
Safe and efficient treatment of neurological disorders and addictions
These compounds target selective expression of alpha-7 and alpha-4-beta-2; nicotinic acetylcholine receptor (nAChR) subtypes that impact cognition, mood, and neuroprotection. Research shows that alpha-4-beta-2 is always associated with addiction. But fewer alpha-7 receptors are expressed if the host suffering from addiction is stressed or suffering from depression. To treat depression, anabaseines can selectively promote alpha-7 receptors while acting as antagonists for alpha-4-beta-2 receptors, which would otherwise interfere with the positive effects of the drug. When individuals suffering from nicotine addiction use nicotine, alpha-4-beta-2 rewards them, creating a dependence effect. To combat nicotine addiction, preliminary research suggests that partial agonists modestly stimulate the same reward circuit of alpha-4-beta-2 receptors that nicotine does, ultimately reducing cravings and blunting the peaks of receptor activation that cigarette smoking or betel quid chewing would create. Unfortunately, available drugs that suppress the rewarding effects of nicotine by inhibiting alpha-4-beta-2 receptors may cause worsened depression or even suicide. By using partial agonists for alpha-7 receptors, drug developers can stimulate alpha-7 receptors unopposed by a concurrent alpha-4-beta-2 inhibitory effect and decrease the function of alpha-4-beta-2 nAChR to treat dependence while counteracting depression.