Identification and pharmacological characterization of 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the α4β2 and α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs)

Strachan, Jon‐Paul; Kombo, David C.; Mazurov, A. A.; Heemstra, Ronald J.; Bhatti, Balwinder S.; Akireddy, Rao; Murthy, Srinivasa; Miao, Lan; Jett, John E; Speake, Jason D.; Bencherif, Merouane

doi:10.1016/j.ejmech.2014.08.019

Cited by 7 publications

(8 citation statements)

References 55 publications

(49 reference statements)

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“…Very recently, 3-cyclopropylcarbonyl-3,6-dazabicyclo[3.1.1]heptane ( 8 , TC-8831) was reported to have K i = 3.0 and 21 nM at α 4 β 2- and α 6/ α 3 β 2 β 3-nAChRs, respectively. 20 Using calcium-flux functional studies, 8 had EC 50 = 80 nM ( E max = 100%) at the α 6/ α 3 β 2 β 3-nAChR. Previous studies had shown that compound 8 ameliorated L-dopa induced dyskinesia (LID) without reducing antiparkinsonian benefits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned nonhuman primates with established LID.…”

Section: Resultsmentioning

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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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%

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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“…TC299423 ( Figure 1 ), one of these compounds, was identified after our previous structure-activity relationship (SAR) studies on other nAChR subtypes ( Breining et al, 2012 ; Zhang et al, 2012 ; Strachan et al, 2014 ) and on α6β2 ∗ nAChRs ( Breining et al, 2009 ; Grady et al, 2010 ; Strachan et al, 2014 ). TC299423 was also analyzed in computational studies on homology models of α6β2 binding sites analogous to those described previously ( Strachan et al, 2014 ). Assays that assessed metabolism were also conducted (discussed below, see Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors

et al. 2017

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(E)-5-(Pyrimidin-5-yl)-1,2,3,4,7,8-hexahydroazocine (TC299423) is a novel agonist for nicotinic acetylcholine receptors (nAChRs). We examined its efficacy, affinity, and potency for α6β2∗ (α6β2-containing), α4β2∗, and α3β4∗ nAChRs, using [125I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal 86Rb+ efflux, [3H]-dopamine release, and [3H]-acetylcholine release. TC299423 displayed an EC50 of 30–60 nM for α6β2∗ nAChRs in patch-clamp recordings and [3H]-dopamine release assays. Its potency for α6β2∗ in these assays was 2.5-fold greater than that for α4β2∗, and much greater than that for α3β4∗-mediated [3H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function, mutant α6 (α6L9′S) nAChR mice, show that TC299423 elicits α6β2∗ nAChR-mediated responses at low doses. Conditioned place preference assays show that low-dose TC299423 also produces significant reward in α6L9′S mice, and modest reward in WT mice, through a mechanism that probably involves α6(non-α4)β2∗ nAChRs. However, TC299423 did not suppress nicotine self-administration in rats, indicating that it did not block nicotine reinforcement in the dosage range that was tested. In a hot-plate test, TC299423 evoked antinociceptive responses in mice similar to those of nicotine. TC299423 and nicotine similarly inhibited mouse marble burying as a measure of anxiolytic effects. Taken together, our data suggest that TC299423 will be a useful small-molecule agonist for future in vitro and in vivo studies of nAChR function and physiology.

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“…27,56–61 Those models display two essential pharmacophoric elements: a cationic center and a hydrogen bond acceptor (HBA). The distance between these two elements can vary from 4–7Å.…”

Section: Resultsmentioning

confidence: 99%

The twin drug approach for novel nicotinic acetylcholine receptor ligands

Tomassoli

Gündisch

2015

Bioorganic & Medicinal Chemistry

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The association of two pharmacophoric entities generates so-called “twin drugs” or dimer derivatives. We applied this approach for the design of a small compound library for the interaction with α4β2* nicotinic acetylcholine receptors (nAChRs). In this compound series, the nAChR ligand N,N-dimethyl-2-(pyridin-3-yloxy)ethan-1-amine 9 served as one pharmacological entity and it was initially kept constant as one part of the “twin” compound. “Twin” compounds with identical or non-identical entities using the “no linker mode” or “overlap” mode were synthesized and evaluated for their nAChR affinities. Compound 17a showed the highest affinity for the α4β2* nAChR subtype (Ki = 0.188 nM) and its (di)fluoro analogs could retain nanomolar affinities, when replacing pyridine as the hydrogen bond acceptor system by mono- or difluoro-phenyls. The “twin drug” approach proved to provide compounds with high affinity and subtype selectivity for α4β2* nAChRs.

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Identification and pharmacological characterization of 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the α4β2 and α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs)

Cited by 7 publications

References 55 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

TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors

The twin drug approach for novel nicotinic acetylcholine receptor ligands

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