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Featured researches published by Gregory J. Gatto.
CNS Neuroscience & Therapeutics | 2008
Patrick M. Lippiello; Jessica S. Beaver; Gregory J. Gatto; John W. James; Kristen G. Jordan; Vincent M. Traina; Jianxun Xie; Merouane Bencherif
Both clinical and preclinical data support a potential therapeutic benefit of modulating the activity of CNS neuronal nicotinic receptors (NNRs) to treat depression and anxiety disorders. Based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC‐5214 (S‐(+) enantiomer of mecamylamine), a noncompetitive NNR antagonist. TC‐5214 demonstrated positive effects in a number of animal models of depression and anxiety. TC‐5214 was active in the forced swim test in rats (minimum effective dose (MED) = 3 mg/kg i.p.), a classical depression model. It was also active in the behavioral despair test in mice (0.1–3.0 mg/kg i.p.), another model of depression. In the social interaction paradigm in rats, a model of generalized anxiety disorder (GAD), TC‐5214 was active at a dose of 0.05 mg/kg s.c. In the light/dark chamber paradigm in rats, a model of GAD and phobia, TC‐5214 was also active at a dose of 0.05 mg/kg s.c. Although TC‐5214 shows modest selectivity among NNR subtypes, the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the α4β2 NNRs. This is supported by the observation of similar effects with α4β2‐selective partial agonists such as cytisine and with α4β2‐selective antagonists such as TC‐2216. TC‐5214 was well tolerated in acute and chronic toxicity studies in mice, rats, and dogs, showed no mutagenicity and displayed safety pharmacology, pharmacokinetic and metabolic profiles appropriate for therapeutic development. Overall, the results support a novel nicotinic cholinergic antagonist mechanism for antidepressant and anxiolytic effects and highlight the potential of NNR antagonists such as TC‐5214 as therapeutics for the treatment of anxiety and depression.
European Journal of Pharmacology | 2000
Merouane Bencherif; Andrew J. Bane; Craig H. Miller; Gary Maurice Dull; Gregory J. Gatto
TC-2559 [(E)-N-Methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine] is a novel nicotinic agonist markedly more selective than recently reported novel nicotinic receptor ligands (selectivity ratio for central nervous system (CNS) to peripheral nervous system (PNS)>4000). TC-2559 competes effectively with [3H]-nicotine binding (K(i)=5 nM) but not with [125I]-bungarotoxin (>50,000 nM). Dopamine release from striatal synaptosomes and ion flux from thalamic synaptosomes indicate that TC-2559 is potent and efficacious in the activation of CNS receptors and significantly reduced glutamate-induced neurotoxicity in vitro. TC-2559 has no detectable effects on muscle and ganglion-type nicotinic acetylcholine receptors at concentrations up to 1 mM. TC-2559 significantly attenuates scopolamine-induced cognitive deficits in a step-through passive avoidance task. Acute and repeated oral dosing of TC-2559 enhances performance in a radial arm maze task. In contrast to the effects of equimolar concentrations of (-) nicotine, TC-2559 does not induce hypothermia and locomotor activity is not enhanced following repeated daily administration of 14 days. TC-2559 has a markedly enhanced CNS-PNS selectivity ratio and an intra-CNS selectivity as evidenced by the improved cognition without increased locomotor activity. The in vitro and in vivo studies in the present study suggest that TC-2559 has the desired profile to be further evaluated as a potential therapeutic agent for neurodegenerative diseases.
Journal of Molecular Neuroscience | 2006
Patrick M. Lippiello; Sharon R. Letchworth; Gregory J. Gatto; Vincent M. Traina; Merouane Bencherif
To date, the primary treatments for Alzheimers disease with proven efficacy have been acetylcholinesterase inhibitors that prevent the hydrolysis of acetylcholine (ACh) in the synaptic cleft, thereby prolonging its activity. Although these agents have some benefit in alleviating cognitive impairment, they have limited clinical utility because of insufficient efficacy and marginal tolerability. Within the last decade, there has been much experimental support for the use of therapeutics that directly target nicotinic ACh receptors (nAChRs) to improve cognitive function and slow neurodegenerative disease progression. These findings have spurred considerable research efforts to develop ligands selective for nAChRs, such as ABT-418 (Arneric et al., 1995), SIB-1553 (Bontempi et al., 2001), TC-2403 (Lippiello et al., 1996), and TC-2559 (Bencherif et al., 2000). There is abundant evidence that nAChR modulators have the potential to alleviate cognitive impairment in demented states. In addition to improving cognitive function, a large body of research implicates a role for nAChRs in neuroprotection, suggesting potential for disease modification. An impact of nAChR agonists on disease progression would provide an advantage over currently available treatments for memory loss. The profile of previous nAChR-targeted clinical candidates has not been adequate to warrant further development owing to poor oral bioavailability, side effects, and/or lack of efficacy. Thus, a challenge in nAChR drug design and development has been the reduction of undesirable effects that result from activity at specific nAChRs in the CNS and PNS, including cardiovascular toxicity, emesis, seizures, and hypothermia.
Journal of Medicinal Chemistry | 2012
Anatoly Mazurov; Lan Miao; Balwinder Singh Bhatti; Jon-Paul Strachan; Srinivasa Rao Akireddy; Srinivasa V. Murthy; David C. Kombo; Yun-De Xiao; Philip S. Hammond; Jenny Z. Zhang; Terry A. Hauser; Kristen G. Jordan; Craig Harrison Miller; Jason D. Speake; Gregory J. Gatto; Daniel Yohannes
Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4β2 nAChR selective agonists comprising a series of N-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4β2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (56, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimers disease.
Bioorganic & Medicinal Chemistry Letters | 2013
Anatoly Mazurov; David C. Kombo; Srinivasa Rao Akireddy; Srinivasa V. Murthy; Terry A. Hauser; Kristen G. Jordan; Gregory J. Gatto; Daniel Yohannes
A novel series of α4β2 nAChR agonists lacking common pyridine or its bioisosteric heterocycle have been disclosed. Essential pharmacophoric elements of the series are exocyclic carbonyl moiety as a hydrogen bond acceptor and secondary amino group within diaza- or azabicyclic scaffold. Computer modeling studies suggested that molecular shape of the ligand also contributes to promotion of agonism. Proof of concept for improving working memory performance in a novel object recognition task has been demonstrated on a representative of the series, 3-propionyl-3,7-diazabicyclo[3.3.0]octane (34).
Journal of Molecular Neuroscience | 2006
Merouane Bencherif; Terry A. Hauser; Kristen G. Jordan; Gregory J. Gatto
The potential therapeutic benefit of nicotinic ligands in a variety of neurodegenerative pathologies involving the CNS has energized research efforts to develop nicotinic acetylcholine receptor (nAChR) subtype-selective ligands (Bencherif and Schmitt, 2005). In particular, there has been a concerted effort to develop nicotinic compounds with selectivity for CNS nAChRs as potential pharmaceutical tools in the management of these disorders. Clinical and experimental data demonstrate a central role for alpha7 and alpha4beta2 nAChRs in cognitive function, sensory processing, mood, and neuroprotection (Bencherif and Schmitt, 2005; Buccafusco et al., 2005). The development of safe alpha7-selective ligands has been hampered by their lack of discrimination with hERG channels and 5-HT3 receptors. We have developed a number of compounds that display nanomolar affinity to the alpha7 and/or the alpha4beta2 receptor. Investigation of alpha7 functional activity showed a full range of activities from antagonists to full agonists without any significant activity at the human 5-HT3 receptor, P450 isozymes, hERG channels, or in the AMES test. Our findings demonstrate that potent and highly selective nAChR ligands can be designed.
Cns Drug Reviews | 2006
Gregory J. Gatto; G Andrees Bohme; William Scott Caldwell; Sharon R. Letchworth; Vincent M. Traina; M. Carmen Obinu; Michel Laville; Michel Reibaud; Laurent Pradier; Geoffrey Dunbar; Merouane Bencherif
Drug Development Research | 2004
Georg Andrees Bohme; Sharon R. Letchworth; Odile Piot-Grosjean; Gregory J. Gatto; Marie-Carmen Obinu; William Scott Caldwell; Michel Laville; Pascale Brunel; Rachel Pellerin; Jean-Pierre Leconte; Arielle Genevois-Borella; Pierre Dubédat; Martine Mazadier; Laurent Pradier; Merouane Bencherif; Jesus Benavides
Archive | 2005
Balwinder Singh Bhatti; Gregory J. Gatto; Jozef Klucik
International Journal of Colorectal Disease | 2007
Tanja Spoettl; Christine Paetzel; Hans Herfarth; Merouane Bencherif; Juergen Schoelmerich; Roland Greinwald; Gregory J. Gatto; Gerhard Rogler