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ABSTRACT: An efficient synthesis of (1R,5S)-6-(5-cyano-3-pyridinyl)-3,6-diaza-bi-cyclo[3.2.0]heptane A-366833, a novel potent selective neuronal nicotinic receptor (NNR) agonist, is described. The enantiomerically pure pharmacophore benzyl (1S,5S)-3,6-diaza-bi-cyclo[3.2.0]heptane-3-carbamate was successfully constructed from benzyl N-allyl-N-(2-hy-droxyimino-ethyl)-carbamate through a convenient approach including an intramolecular [1,3]-dipolar cycloaddition, reductive ring-opening reaction, chiral resolution, and intra-molecular cyclization. Subsequent N-arylation of the pharmacophore with 3-bromo-5-cyano-pyridine and N-Cbz deprotection with trifluoroacetic acid furnished A-366833. In the search for novel therapeutic compounds to safely treat both acute and chronic pain, a number of novel approaches to pain relief are currently under investigation. One of the most promising approaches is the use of selective neuronal nicotinic receptor (NNR) agonists as analgesics [1]. A diversity of NNR subtypes are widely distributed throughout the central and peripheral nervous systems. The centrally expressed α4β2 subtype is understood to be an important target involved in mediating the analgesic re-sponse elicited by NNR agonists [2]. The discovery of epibatidine, an NNR agonist with extremely po-tent analgesic activity [3], fueled great interest in research directed toward identifying safe and effica-cious analgesics acting through an NNR-mediated mechanism. At Abbott Laboratories, ABT-594 was discovered to possess broad-spectrum antinociceptive activity in preclinical assays of acute and chronic pain and was advanced to clinical development [4]. To further understand the NNR subtypes that me-diate analgesia vs. adverse events, and to develop a second-generation NNR-based analgesic, a series of enantiopure-fused azetidines have been prepared. A-366833 was found to be a selective α4β2 ago-nist with broad-spectrum analgesic activity and an improved safety profile relative to ABT-594 [5]. Here, we disclose the synthesis of enantiomerically pure benzyl (1S,5S)-3,6-diaza-bicyclo[3.2.0]hep-tane-3-carbamate and its further application in the efficient synthesis of A-366833.
Pure Appl. Chem. 01/2041; 77:2041-2045.
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Michael R Schrimpf,
Kevin B Sippy,
Clark A Briggs, David J Anderson,
Tao Li,
Jianguo Ji,
Jennifer M Frost,
Carol S Surowy,
William H Bunnelle,
Murali Gopalakrishnan,
Michael D Meyer
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ABSTRACT: The well-known interferon-inducer tilorone was found to possess potent affinity for the agonist site of the α7 neuronal nicotinic receptor (K(i)=56 nM). SAR investigations determined that both basic sidechains are essential for potent activity, however active monosubstituted derivatives can also be prepared if the flexible sidechains are replaced with conformationally rigidified cyclic amines. Analogs in which the fluorenone core is replaced with either dibenzothiophene-5,5-dioxide or xanthenone also retain potent activity.
Bioorganic & medicinal chemistry letters 02/2012; 22(4):1633-8. · 2.65 Impact Factor
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Marc J C Scanio,
Lei Shi,
William H Bunnelle, David J Anderson,
Rosalind J Helfrich,
John Malysz,
Kirsten K Thorin-Hagene,
Ceclia E Van Handel,
Kennan C Marsh,
Chih-Hung Lee,
Murali Gopalakrishnan
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ABSTRACT: A series of diazabicyclo[3.3.0]octane substituted pyridines and pyrazines was synthesized and characterized at the α4β2 neuronal nicotinic acetylcholine receptor (nAChR). The compounds were designed to mimic the profile of ABT-089, high affinity binding ligand for the α4β2 nAChR, with limited agonist activity. Carboxamide derivatives of 3-(diazabicyclo[3.3.0]octane)-substituted pyridines or 2-(diazabicyclo[3.3.0]octane)-substituted pyrazines were found to have the desired binding and activity profile. The structure-activity relationship of these compounds is presented.
Journal of Medicinal Chemistry 09/2011; 54(21):7678-92. · 4.80 Impact Factor
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Jinhe Li,
Suzanne L Mathieu,
Richard Harris,
Jianguo Ji, David J Anderson,
John Malysz,
William H Bunnelle,
Jeffrey F Waring,
Kennan C Marsh,
Anwar Murtaza,
Lisa M Olson,
Murali Gopalakrishnan
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ABSTRACT: Immunological responses to protect against excessive inflammation can be regulated by the central nervous system through the cholinergic anti-inflammatory pathway wherein acetylcholine released from vagus nerves can inhibit inflammatory cytokines. Although a role for the α7 nicotinic acetylcholine receptor (α7 nAChR) in mediating this pathway has been suggested, pharmacological modulation of the pathway by selective agonists remains to be further elucidated. In this study, the role of α7 nAChRs in the regulation of TNF-α release was investigated using high affinity and selective α7 nAChR agonists in mouse peritoneal macrophage and human whole blood in vitro, and in mouse serum in vivo. In mouse peritoneal macrophages, LPS-induced TNF-α release in vitro was inhibited by a selective α7 nAChR agonist, A-833834 (5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole), and that effect was attenuated by α7 nAChR antagonist methyllycaconitine. The inhibitory effect of A-833834 on LPS-induced TNF-α release was also observed in human whole blood in vitro. I.v. LPS-induced TNF-α release in mouse serum was attenuated following i.p. administration of A-833834. Similarly, i.v. LPS-induced TNF-α release in mouse serum was also attenuated following i.p. administration of A-585539, another α7 nAChR agonist with limited brain penetration, suggesting that these effects are mediated by peripheral α7 nAChRs. A-833834 was also efficacious in suppressing TNF-α release in mouse serum following oral administration in zymosan-induced peritonitis. These studies collectively demonstrate that selectively targeting α7 nAChRs could offer a novel therapeutic modality to treat acute and chronic inflammatory disease states.
Journal of neuroimmunology 09/2011; 239(1-2):37-43. · 2.84 Impact Factor
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Di Zhang,
Rama Thimmapaya,
Xu-Feng Zhang, David J Anderson,
John L Baranowski,
Marc Scanio,
Arturo Perez-Medrano,
Sridhar Peddi,
Zhi Wang,
Jyoti R Patel,
David A DeGoey,
Murali Gopalakrishnan,
Prisca Honore,
Betty B Yao,
Carol S Surowy
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ABSTRACT: KCNQ2/3 voltage-gated potassium channels conduct low-threshold, slowly activating and non-inactivating currents to repolarize the neuronal resting membrane potential. The channels negatively regulate neuronal excitability and KCNQ2/3 openers are efficacious in hyperexcited states such as epilepsy and pain. We developed and utilized thallium influx assays to profile novel KCNQ2/3 channel openers with respect to selectivity across KCNQ subtypes and on requirement for tryptophan 236 of KCNQ2, a critical residue for activity of the KCNQ opener retigabine. Using distinct chemical series of openers, a quinazolinone series showed relatively poor selectivity across multiple KCNQ channels and lacked activity at the KCNQ2(W236L) mutant channel. In contrast, several novel benzimidazole openers showed selectivity for KCNQ2/3 and KCNQ2 and retain activity at KCNQ2(W236L). Profiling of several hundred KCNQ2/3 openers across multiple diverse chemical series revealed that openers show differential degrees of selectivity across subtypes, with selectivity most difficult to achieve against KCNQ2. In addition, we report the significant finding that KCNQ openers can pharmacologically differentiate between homomeric and heteromeric channels containing subtypes in common. Moreover, most openers assayed were dependent on the W236 for activity, whereas only a small number appear to use a distinct mechanism. Collectively, we provide novel insights into the molecular pharmacology of KCNQ channels by demonstrating differential selectivity and site of action for KCNQ2/3 openers. The high-throughput thallium influx assays should prove useful for rapid characterization of KCNQ openers and in guiding efforts to identify selective compounds for advancement towards the clinic.
Journal of neuroscience methods 06/2011; 200(1):54-62. · 2.30 Impact Factor
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ABSTRACT: α7 nicotinic acetylcholine receptors (nAChRs) are characterized by relatively low ACh sensitivity, rapid activation, and fast desensitization kinetics. ACh/agonist evoked currents at the α7 nAChR are transient, and, typically, calcium flux responses are difficult to detect using conventional fluorometric assay techniques. One approach to study interactions of agonists with the α7 nAChR is by utilizing positive allosteric modulators (PAMs). In this study, we demonstrate that inclusion of type II PAMs such as PNU-120596, but not type I, can enable detection of endogenous α7 nAChR-mediated calcium responses in human neuroblastoma (IMR-32) cells. Using this approach, we characterized the pharmacological profile of nicotine, epibatidine, choline, and other nAChR agonists such as PNU-282987, SSR-180711, GTS-21, OH-GTS21, tropisetron, NS6784, and A-582941. The rank order potency of agonists well correlated with α7 nAChR binding affinities measured in brain membranes. Inhibition of calcium response by methyllycaconitine in the presence of increasing concentrations of PNU-282987 or PNU-120596 revealed that the IC(50) value of methyllycaconitine was sensitive to varying concentrations of the agonist, but not that of the PAM. This format demonstrated the feasibility of this approach for high-throughput screening to identify small molecule, PAMs, which were further confirmed in electrophysiological assays of human α7 nAChR expressed in oocytes.
Assay and Drug Development Technologies 02/2011; 9(6):635-45. · 1.73 Impact Factor
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John Malysz, David J Anderson,
Jens H Grønlien,
Jianguo Ji,
William H Bunnelle,
Monika Håkerud,
Kirten Thorin-Hagene,
Hilde Ween,
Rosalind Helfrich,
Min Hu, [......],
Pamela S Puttfarcken,
Clark A Briggs,
Jinhe Li,
Michael D Meyer,
Tino Dyhring,
Philip K Ahring,
Elsebet Ø Nielsen,
Dan Peters,
Daniel B Timmermann,
Murali Gopalakrishnan
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ABSTRACT: Enhancement of alpha7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective alpha7 nAChR agonist, 5-(6-[(3R)-1-azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107). ABT-107 displayed high affinity binding to alpha7 nAChRs [rat or human cortex, [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539), K(i) = 0.2-0.6 nM or [(3)H]methyllycaconitine (MLA), 7 nM] that was at least 100-fold selective versus non-alpha7 nAChRs and other receptors. Functionally, ABT-107 did not evoke detectible currents in Xenopus oocytes expressing human or nonhuman alpha3beta4, chimeric (alpha6/alpha3)beta4, or 5-HT(3A) receptors, and weak or negligible Ca(2+) responses in human neuroblastoma IMR-32 cells (alpha3* function) and human alpha4beta2 and alpha4beta4 nAChRs expressed in human embryonic kidney 293 cells. ABT-107 potently evoked human and rat alpha7 nAChR current responses in oocytes (EC(50), 50-90 nM total charge, approximately 80% normalized to acetylcholine) that were enhanced by the positive allosteric modulator (PAM) 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (A-867744). In rat hippocampus, ABT-107 alone evoked alpha7-like currents, which were inhibited by the alpha7 antagonist MLA. In dentate gyrus granule cells, ABT-107 enhanced spontaneous inhibitory postsynaptic current activity when coapplied with A-867744. In the presence of an alpha7 PAM [A-867744 or N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-120596)], the addition of ABT-107 elicited MLA-sensitive alpha7 nAChR-mediated Ca(2+) signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity alpha7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.
Journal of Pharmacology and Experimental Therapeutics 09/2010; 334(3):863-74. · 3.83 Impact Factor
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R Scott Bitner,
William H Bunnelle,
Michael W Decker,
Karla U Drescher,
Kathy L Kohlhaas,
Stella Markosyan,
Kennan C Marsh,
Arthur L Nikkel,
Kaitlin Browman,
Rich Radek, David J Anderson,
Jerry Buccafusco,
Murali Gopalakrishnan
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ABSTRACT: We previously reported that alpha7 nicotinic acetylcholine receptor (nAChR) agonism produces efficacy in preclinical cognition models correlating with activation of cognitive and neuroprotective signaling pathways associated with Alzheimer's disease (AD) pathology. In the present studies, the selective and potent alpha7 nAChR agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole (ABT-107) was evaluated in behavioral assays representing distinct cognitive domains. Studies were also conducted to address potential issues that may be associated with the clinical development of an alpha7 nAChR agonist. Specifically, ABT-107 improved cognition in monkey delayed matching to sample, rat social recognition, and mouse two-trial inhibitory avoidance, and continued to improve cognitive performance at injection times when exposure levels continued to decline. Rats concurrently infused with ABT-107 and donepezil at steady-state levels consistent with clinical exposure showed improved short-term recognition memory. Compared with nicotine, ABT-107 did not produce behavioral sensitization in rats or exhibit psychomotor stimulant activity in mice. Repeated (3 days) daily dosing of ABT-107 increased extracellular cortical acetylcholine in rats, whereas acute administration increased cortical extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation in mice, neurochemical and biochemical events germane to cognitive function. ABT-107 increased cortical phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3, a primary tau kinase associated with AD pathology. In addition, continuous infusion of ABT-107 in tau/amyloid precursor protein transgenic AD mice reduced spinal tau hyperphosphorylation. These findings show that targeting alpha7 nAChRs may have potential utility for symptomatic alleviation and slowing of disease progression in the treatment AD, and expand the understanding of the potential therapeutic viability associated with the alpha7 nAChR approach in the treatment of AD.
Journal of Pharmacology and Experimental Therapeutics 09/2010; 334(3):875-86. · 3.83 Impact Factor
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Tao Li,
William H Bunnelle,
Keith B Ryther, David J Anderson,
John Malysz,
Rosalind Helfrich,
Jens H Grønlien,
Monika Håkerud,
Dan Peters,
Michael R Schrimpf,
Murali Gopalakrishnan,
Jianguo Ji
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ABSTRACT: Biaryl substituted 2,5-diazabicyclo[2.2.1]heptanes have been synthesized and tested for their affinity toward alpha7 neuronal nicotinic receptors (NNRs). SAR studies established that 5-N-methyl substituent, heteroaryl linker and the nature of terminal aryl group are critical for the ligand to achieve potent alpha7 NNR agonist activity.
Bioorganic & medicinal chemistry letters 06/2010; 20(12):3636-9. · 2.65 Impact Factor
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ABSTRACT: A series of alpha7 neuronal nicotinic acetylcholine receptor ligands were designed based on a structural combination of a potent, but non-selective ligand, epibatidine, with a selective lead structure, 2. Three series of compounds in which aryl moieties were attached via a linker to different positions on the core structure were studied. A potent and functionally efficacious analog, (3aR,6aS)-2-(6-phenylpyridazin-3-yl)-5-(pyridin-3-ylmethyl)octahydropyrrolo[3,4-c]pyrrole (3a), was identified.
Bioorganic & medicinal chemistry letters 11/2009; 20(1):104-7. · 2.65 Impact Factor
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Clark A Briggs,
Jens Halvard Grønlien,
Peter Curzon,
Daniel B Timmermann,
Hilde Ween,
Kirsten Thorin-Hagene,
Paige Kerr, David J Anderson,
John Malysz,
Tino Dyhring,
Gunnar M Olsen,
Dan Peters,
William H Bunnelle,
Murali Gopalakrishnan
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ABSTRACT: Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved.
Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm.
NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941.
Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.
British Journal of Pharmacology 11/2009; 158(6):1486-94. · 4.41 Impact Factor
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William H Bunnelle,
Karin R Tietje,
Jennifer M Frost,
Dan Peters,
Jianguo Ji,
Tao Li,
Marc J C Scanio,
Lei Shi, David J Anderson,
Tino Dyhring,
Jens H Grønlien,
Hilde Ween,
Kirsten Thorin-Hagene,
Michael D Meyer
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ABSTRACT: A series of 5-(pyridine-3-yl)octahydropyrrolo[3,4-c]pyrroles have been prepared that exhibit high affinity to alpha4beta2 and/or alpha7 nicotinic acetylcholine receptors (nAChRs). Simple substitution patterns have been identified that allow construction of ligands that are highly selective for either nAChR subtype. The effects of substitution on subtype selectivity provide some insight into the differences in the ligand binding domains of the alpha4beta2 and alpha7 receptors, especially in regions removed from the cation binding pocket.
Journal of Medicinal Chemistry 07/2009; 52(14):4126-41. · 4.80 Impact Factor
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ABSTRACT: alpha4beta2 neuronal nicotinic receptors (nAChRs) can exist in high and low sensitivity states possibly due to distinct stoichiometries during subunit assembly: (alpha4)(2)(beta2)(3) pentamer (high sensitivity, HS) and (alpha4)(3)(beta2)(2) pentamer (low sensitivity, LS). To determine if there is a linkage between HS or LS states and receptor-mediated responses in brain, we profiled several clinically studied alpha4beta2* nAChR agonists for the displacement of radioligand binding to alpha4beta2 [(3)H]-cytisine sites in rat brain membranes, effects on stimulation of [(3)H]-dopamine release from slices of rat prefrontal cortex and striatum, and activation of HS and LS human alpha4beta2 nAChRs expressed in Xenopus laevis oocytes. Binding affinities (pK(i)) and potency (pEC(50)) values for [(3)H]-dopamine release closely correlated with a rank order: varenicline>(-)-nicotine>AZD3480>dianicline congruent with ABT-089. Further, a good correlation was observed between [(3)H]-dopamine release and HS alpha4beta2 pEC(50) values, but not between [(3)H]-dopamine release and LS alpha4beta2. The relative efficacies of the agonists ranged from full to partial agonists. Varenicline behaved as a partial agonist in stimulating [(3)H]-dopamine release and activating both HS and LS alpha4beta2 nAChRs expressed in oocytes. Conversely, ABT-089, AZD3480 and dianicline exhibited little efficacy at LS alpha4beta2 (<5%), were more effective at HS alpha4beta2 nAChRs, and in stimulating cortical and striatal [(3)H]-dopamine release >or=30%. In the presence of alpha-conotoxin MII to block alpha6beta2* nAChRs, the alpha4beta2* alpha-conotoxin-insensitive [(3)H]-dopamine release stimulated by these ligands correlates well with their interactions at HS, but not LS. In summary, this study provides support for HS alpha4beta2* nAChR involvement in neurotransmitter release.
Biochemical pharmacology 06/2009; 78(7):844-51. · 4.25 Impact Factor
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John Malysz,
Jens Halvard Grønlien, David J Anderson,
Monika Håkerud,
Kirsten Thorin-Hagene,
Hilde Ween,
Caroline Wetterstrand,
Clark A Briggs,
Ramin Faghih,
William H Bunnelle,
Murali Gopalakrishnan
[show abstract]
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ABSTRACT: Targeting alpha7 neuronal acetylcholine receptors (nAChRs) with selective agonists and positive allosteric modulators (PAMs) is considered a therapeutic approach for managing cognitive deficits in schizophrenia and Alzheimer's disease. In this study, we describe a novel type II alpha7 PAM, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), that exhibits a unique pharmacological profile. In oocytes expressing alpha7 nAChRs, A-867744 potentiated acetylcholine (ACh)-evoked currents, with an EC(50) value of approximately 1 microM. At highest concentrations of A-867744 tested, ACh-evoked currents were essentially nondecaying. At lower concentrations, no evidence of a distinct secondary component was evident in contrast to 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), another type II alpha7 PAM. In the presence of A-867744, ACh concentration responses were potentiated by increases in potency, Hill slope, and maximal efficacy. When examined in rat hippocampus CA1 stratum radiatum interneurons or dentate gyrus granule cells, A-867744 (10 microM) increased choline-evoked alpha7 currents and recovery from inhibition/desensitization, and enhanced spontaneous inhibitory postsynaptic current activity. A-867744, like other alpha7 PAMs tested [1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)urea (NS1738), TQS, and 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596)], did not displace the binding of [(3)H]methyllycaconitine to rat cortex alpha7(*) nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539) in rat cortex, with a K(i) value of 23 nM. A-867744 neither increased agonist-evoked responses nor displaced the binding of [(3)H]A-585539 in an alpha7/5-hydroxytryptamine(3) (alpha7/5-HT(3)) chimera, suggesting an interaction distinct from the alpha7 N terminus or M2-3 loop. In addition, A-867744 failed to potentiate responses mediated by 5-HT(3A) or alpha3beta4 and alpha4beta2 nAChRs. In summary, this study identifies a novel and selective alpha7 PAM showing activity at recombinant and native alpha7 nAChRs exhibiting a unique pharmacological interaction with the receptor.
Journal of Pharmacology and Experimental Therapeutics 05/2009; 330(1):257-67. · 3.83 Impact Factor
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ABSTRACT: Several N-pyridin-3-yl spirobicyclic diamines, designed as conformationally restricted analogs of tebanicline (ABT-594), were synthesized as novel ligands for nicotinic acetylcholine receptors (nAChR). The spirocyclic compounds exhibited weaker binding affinity, than other constrained analogs in accord with a pharmacophore model. Nevertheless, some (1a, 1b) possessed (partial) agonist potencies comparable to nicotine at the alpha4beta2 subtype, but with greatly improved selectivity relative to the alpha3beta4* nAChR.
Bioorganic & medicinal chemistry letters 03/2009; 19(6):1682-5. · 2.65 Impact Factor
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ABSTRACT: The nicotinic acetylcholine receptors (nAChRs) play critical roles in neuronal transmission and modulation. Among the diverse nAChRs, the alpha7 subtype has been considered as a potential therapeutic target for treating cognitive deficits associated with neuropsychiatric and neurodegenerative diseases. Although a number of mechanisms including neurotransmitter and biochemical effects linking alpha7 nAChR activation and cognitive function are beginning to be described, the underlying molecular processes especially following repeated administration remain unclear. To address this, we have performed gene expression analysis in rats treated with nicotine and a selective alpha7 nAChR agonist, PNU-282987. Our results showed significant overlap in gene expression changes induced by PNU-282987 and nicotine, suggesting convergent pathways triggered by these compounds. Treatment with nicotine also resulted in regulation of a number of genes that were not regulated by PNU-282987, consistent with the interaction of nicotine with other nAChRs beyond the alpha7 subtype. Interestingly, these gene expression changes were observed 24 h post-dose, suggesting that both nicotine and PNU-282987 cause protracted changes in gene expression. Overall, our results identify gene expression changes that may contribute to further defining the roles of nAChR activation in cognitive function.
Neuroscience Research 04/2008; 60(3):266-74. · 2.25 Impact Factor
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Karin R Tietje, David J Anderson,
R Scott Bitner,
Eric A Blomme,
Paul J Brackemeyer,
Clark A Briggs,
Kaitlin E Browman,
Dagmar Bury,
Peter Curzon,
Karla U Drescher, [......],
Pamela S Puttfarcken,
Richard J Radek,
Holly M Robb,
Eva Spies,
Kirsten Thorin-Hagene,
Jeffrey F Waring,
Hilde Ween,
Hongyu Xu,
Murali Gopalakrishnan,
William H Bunnelle
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ABSTRACT: Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine alpha7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A-582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A-582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short-term recognition memory, memory consolidation, and sensory gating deficit. A-582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that alpha7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.
CNS Neuroscience & Therapeutics 02/2008; 14(1):65-82. · 4.44 Impact Factor
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ABSTRACT: Receptor binding was characterized for [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane ([(3)H]A-585539), a selective high-affinity alpha7 nicotinic acetylcholine receptor (nAChR) agonist with rapid kinetics, low nonspecific binding, and high specific activity. At 4 degrees C, the association was monophasic and rapid (t((1/2)) = 8.0 min); dissociation was slower (t((1/2)) = 64.2 min). The K(d) in rat brain at 4 degrees C was 0.063 nM, whereas at 22 and 37 degrees C, the K(d) values were 0.188 and 0.95 nM, respectively. In contrast, the B(max) (34 fmol/mg protein) was unaffected by temperature. In human cortex, [(3)H]A-585539 bound with a K(d) of 0.066 nM and a B(max) of 5.8 fmol/mg protein at 4 degrees C, whereas under similar conditions, specific [(3)H]methyllycaconitine ([(3)H]MLA) binding was not measurable. A number of agonist and antagonist nAChR ligands displaced binding to rat brain membranes with rank order of affinity similar to that for [(3)H]MLA, and in general, a 5 to 10-fold higher affinity was observed for [(3)H]A-585539 binding. There was also a good correlation of K(i) values between [(3)H]A-585539 binding to rat brain and human cortex. The use of a alpha7/5-hydroxytryptamine type-3 chimera revealed that the N-terminal domain of alpha7 nAChR was sufficient to faithfully reproduce the pharmacology of [(3)H]A-585539 binding. Autoradiographic studies comparing [(3)H]A-585539 and [(125)I]alpha-bungarotoxin revealed a similar pattern of labeling in the rat. In summary, [(3)H]A-585539 was shown to have excellent binding characteristics in rat and human brain and represents the first high-affinity alpha7 agonist radioligand with utility in the characterization of this important nAChR subtype that is targeted toward ameliorating cognitive deficits underlying neuropsychiatric and neurodegenerative disorders.
Journal of Pharmacology and Experimental Therapeutics 02/2008; 324(1):179-87. · 3.83 Impact Factor
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Jianguo Ji,
Michael R Schrimpf,
Kevin B Sippy,
William H Bunnelle,
Tao Li, David J Anderson,
Connie Faltynek,
Carol S Surowy,
Tino Dyhring,
Philip K Ahring,
Michael D Meyer
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ABSTRACT: A series of novel, potent neuronal nicotinic acetylcholine receptor (nAChR) ligands derived from 3,6-diazabicyclo[3.2.0]heptane have been synthesized and evaluated for binding affinity and agonist activity at the alpha4beta2 nAChR subtype. Structure-activity relationship studies of these novel nAChR ligands focused on substitution effects on the pyridine ring, as well as stereo- and regiochemical influences of the 3,6-diazabicyclo[3.2.0]heptane core. Small 5-substituents on the pyridine ring had a modest impact on the binding affinities and functional activities. 6-Bromo, 6-chloro, and 6-methyl substituents on the pyridine ring led to increased binding affinities and improved functional activities. Most of the 6-N-pyridinyl-substituted 3,6-diazabicyclo[3.2.0]heptanes are selective for the alpha4beta2 nAChR subtype. Compounds (1R,5S)-25, (1R,5S)-55, and (1R,5S)-56 were virtually inactive as agonists at the halpha3beta4 nAChR but retained potency and efficacy at the halpha4beta2 nAChR subtype. 3-N-Pyridinyl-substituted series demonstrated more complex SAR. (1R,5R)-39, (1R,5R)-41, and (1R,5R)-42 were found to be much more potent at the halpha3beta4 nAChR subtype, whereas (1R,5R)-38 and (1R,5R)-40 were very selective at the halpha4beta2 nAChR subtype. The SAR studies of these novel ligands led to the discovery of several compounds with interesting in vitro pharmacological profiles.
Journal of Medicinal Chemistry 12/2007; 50(22):5493-508. · 5.25 Impact Factor
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Jianguo Ji,
William H Bunnelle, David J Anderson,
Connie Faltynek,
Tino Dyhring,
Philip K Ahring,
Lynne E Rueter,
Peter Curzon,
Michael J Buckley,
Kennan C Marsh,
Anita Kempf-Grote,
Michael D Meyer
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ABSTRACT: 5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([3H]-cytisine) with Ki value of 3.1 nM and exhibits agonist selectivity at alpha4beta2 nAChR relative to the alpha3beta4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 micromol/kg (i.p.). In addition, A-366833 demonstrated significant effects in acute thermal pain (6.2-19.0 micromol/kg, i.p.), formalin (1.9-19 micromol/kg i.p.) and SNL (1.9-19 micromol/kg i.p.) models. The systemic effects of A-366833 were attenuated by pretreatment with mecamylamine (5 micromol/kg i.p.) in both the formalin and SNL models, suggesting that the analgesic effects of A-366833 in models of persistent nociceptive and neuropathic pain are mediated by activation of nAChRs. Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at alpha4beta2 vs. alpha3beta4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects.
Biochemical Pharmacology 11/2007; 74(8):1253-62. · 4.70 Impact Factor
