6′-Methylpyrido[3,4-b]norhomotropane: synthesis and outstanding potency in relation to the α4β2 nicotinic receptor pharmacophore model

Kanne, David B.; Tomizawa, M.; Durkin, Kathleen A.; Casida, John E.

doi:10.1016/j.bmcl.2004.12.069

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…6–8 In 2006, we reported the synthesis and pharmacological characterization of (+)- and (−)-PHT. 9 We found that PHT and (+)- and (−)-PHT had K i values of 6.2, 1.29, and 346 nM, respectively, for inhibition of [ 3 H]epibatidine binding to nAChRs.…”

Section: Resultsmentioning

confidence: 99%

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In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (−)-Pyrido[3,4]homotropane [(+)- and (−)-PHT]: (+)-PHT Is a Potent and Selective Full Agonist at α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors

Carroll

Navarro

Mascarella

et al. 2015

ACS Chem. Neurosci.

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Pyrido[3,4]homotropane (PHT) is a conformationally rigid, high affinity analogue of nicotine. (+)-PHT was previously shown to be 266 times more potent than (−)-PHT for inhibition of [3H]epibatidine binding to nAChRs but had no antinociceptive activity in mouse tail-flick or hot-plate tests and was not a nicotinic antagonist even when administered intrathecally. While (−)-PHT had no agonist activity, it was a potent, nicotinic antagonist in the test. Here, electrophysiological studies with rat nAChRs show (+)-PHT to be a low eficacy partial agonist selective for α4β2-nAChRs, relative to α3β4-nAChRs (15-fold) and α7-nAChRs (45-fold). (−)-PHT was an antagonist with selectivity for α3β4, relative to α4β2-(3-fold) and α7- (11-fold) nAChRs. In [3H]DA release studies in mice, (+)-PHT was 10-fold more potent than (−)-PHT at α4β2*-nAChRs and 30-fold more potent at α6β2*-nAChRs. Studies using α5KO mice suggested that much of the activity at α4β2*-nAChRs is mediated by the α4β2α5-nAChR subtype. In conditioned place preference studies, (−)-PHT was more potent than (+)-PHT in blocking nicotine reward. Off-target screens showed (+)- and (−)-PHT to be highly selective for nAChRs. The high potency, full agonism of (+)- and (−)-PHT at α6*-nAChR contrasts with the partial agonism observed for α4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.

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Section: Resultsmentioning

confidence: 99%

“…6–8 In 2006 we synthesized (+)- and (−)-PHT (Figure 1) and reported that there was a large difference in the ability of the two enantiomers to compete with [ 3 H]epibatidine binding in rat brain. 9 In addition, their in vivo pharmacological properties in mice were not consistent with their nAChR binding affinities.…”

mentioning

confidence: 99%

In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (−)-Pyrido[3,4]homotropane [(+)- and (−)-PHT]: (+)-PHT Is a Potent and Selective Full Agonist at α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors

Carroll

Navarro

Mascarella

et al. 2015

ACS Chem. Neurosci.

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“…[61] Recently, its methyl derivative 4 b (R = Me) has also been prepared [62] and found to be three times more potent than 4 a in displacing [ 3 H]nicotine from the a4b2* receptor of mouse fibroblast M10 cells (K i = 0.39 nm and 1.3 nm, respectively). Following the same synthetic pathway used for the racemate, but using an enantiopure reactant, Carroll and co-workers were able to obtain the enantiomers of 4 a and to assess their functional properties.…”

Section: Agonistsmentioning

confidence: 98%

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

et al. 2007

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The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

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“…Three different strategies for analogue design have emerged, and these include: 1) Modification of the pyrrolidine ring generated a number of promising nAChR ligands. For example, the rigid nicotine analogue 4 22 displayed a K i value of 1.3 nM in the displacement of [ 3 H]-nicotine at α4β2* receptors from mouse fibroblast M10 cells. Compound 5 (RJR-2403)23,24 is an α4β2-nAChR-selective partial agonist with a K i value of 26 nM, and it has been investigated for use in the treatment of cognitive dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Chemistry and Pharmacological Characterization of Novel Nitrogen Analogues of AMOP-H-OH (Sazetidine-A, 6-[5-(Azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as α4β2-Nicotinic Acetylcholine Receptor-Selective Partial Agonists

et al. 2010

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In order to advance therapeutic applications of nicotinic ligands, continuing research efforts are being directed toward the identification and characterization of novel nicotinic acetylcholine receptor (nAChR) ligands that are both potent and subtype selective. Herein we report the synthesis and pharmacological evaluation of members of a new series of 3-alkoxy-5-aminopyridine derivatives that display good selectivity for the α4β2-nAChR subtype based on ligand binding and functional evaluations. The most potent ligand in this series, compound 64, showed high radioligand binding affinity and selectivity for rat α4β2-nAChR with a Ki value of 1.2 nM and 4700-fold selectivity for α4β2-over α3β4-nAChR, and ~100-fold selectivity for functional, high-sensitivity, human α4β2-nAChR over α3β4*-nAChR. In the mouse forced swim test, compound 64 exhibited antidepressant-like effects. Structure-activity relationship (SAR) analyses suggest that the introduction of additional substituents to the amino group present on the pyridine ring of the N-demethylated analogue of compound 17 can provide potent α4β2-nAChR-selective ligands for possible use in treatment of neurological and psychiatric disorders including depression.

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6′-Methylpyrido[3,4-b]norhomotropane: synthesis and outstanding potency in relation to the α4β2 nicotinic receptor pharmacophore model

Cited by 12 publications

References 35 publications

In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (−)-Pyrido[3,4]homotropane [(+)- and (−)-PHT]: (+)-PHT Is a Potent and Selective Full Agonist at α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors

In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (−)-Pyrido[3,4]homotropane [(+)- and (−)-PHT]: (+)-PHT Is a Potent and Selective Full Agonist at α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

Chemistry and Pharmacological Characterization of Novel Nitrogen Analogues of AMOP-H-OH (Sazetidine-A, 6-[5-(Azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as α4β2-Nicotinic Acetylcholine Receptor-Selective Partial Agonists

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