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Ivy F Carroll - One of the best experts on this subject based on the ideXlab platform.

  • nicotinic acetylcholine receptor accessory subunits determine the activity profile of Epibatidine derivatives
    Molecular Pharmacology, 2020
    Co-Authors: Lu Wenchi Corrie, Lance R. Mcmahon, Ivy F Carroll, Clare Stokes, Jenny L Wilkerson, Roger L Papke
    Abstract:

    Epibatidine is a potent analgetic agent with very high affinity for brain nicotinic acetylcholine receptors (nAChR). We determined the activity profiles of three Epibatidine derivatives, RTI-36, RTI-76, and RTI-102, which have affinity for brain nAChR equivalent to that of Epibatidine but reduced analgetic activity. RNAs coding for nAChR monomeric subunits and/or concatamers were injected into Xenopus oocytes to obtain receptors of defined subunit composition and stoichiometry. The Epibatidine analogs produced protracted activation of high sensitivity (HS) α4- and α2-containing receptors with the stoichiometry of 2alpha:3beta subunits but not low sensitivity (LS) receptors with the reverse ratio of alpha and beta subunits. Although not strongly activated by the Epibatidine analogs, LS α4- and α2-containing receptors were potently desensitized by the Epibatidine analogs. In general, the responses of α4(2)β2(2)α5 and β3α4β2α6β2 receptors were similar to those of the HS α4β2 receptors. RTI-36, the analog closest in structure to Epibatidine, was the most efficacious of the three compounds, also effectively activating α7 and α3β4 receptors, albeit with lower potency and less desensitizing effect. Although not the most efficacious agonist, RTI-76 was the most potent desensitizer of α4- and α2-containing receptors. RTI-102, a strong partial agonist for HS α4β2 receptors, was effectively an antagonist for LS α4β2 receptors. Our results highlight the importance of subunit stoichiometry and the presence or absence of specific accessory subunits for determining the activity of these drugs on brain nAChR, affecting the interpretation of in vivo studies since in most cases these structural details are not known. SIGNIFICANCE STATEMENT Epibatidine and related compounds are potent ligands for the high-affinity nicotine receptors of the brain, which are therapeutic targets and mediators of nicotine addiction. Far from being a homogeneous population, these receptors are diverse in subunit composition and vary in subunit stoichiometry. We show the importance of these structural details for drug activity profiles, which present a challenge for the interpretation of in vivo experiments since conventional methods, such as in situ hybridization and immunohistochemistry, cannot illuminate these details.

  • Epibatidine analogs synthesized for characterization of nicotinic pharmacophores a review
    Heterocycles, 2009
    Co-Authors: Ivy F Carroll
    Abstract:

    - In 1992 Daly and co-workers reported the isolation of a new natural product, Epibatidine. Future studies showed that Epibatidine was an nAChR ligand with analgesic potency 200-400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine's unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of Epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the α4β2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction.

  • Epibatidine structure activity relationships
    Bioorganic & Medicinal Chemistry Letters, 2004
    Co-Authors: Ivy F Carroll
    Abstract:

    Epibatidine is a potent but nonselective nAChR agonist. Its biological effects appear to be mediated largely by α4β2 nAChRs. Surprisingly, only a limited number of Epibatidine analogues have been synthesized and evaluated in in vitro assays. Even fewer analogues have received in vivo pharmacological evaluation. In this paper, SAR studies directed toward Epibatidine analogues will be reviewed.

  • synthesis of bridged analogs of Epibatidine 3 chloro 5 7 8 9 9a 10 hexahydro 7 10 methanopyrrolo 1 2 b 2 6 naphthyridine and 2 chloro 5 5a 6 7 8 10 hexahydro 5 8 methanopyrrolo 2 1 b 1 7 naphthyridine
    Tetrahedron Letters, 2001
    Co-Authors: Lawrence E Brieaddy, Billy R. Martin, M. Imad Damaj, Hernan A Navarro, Wayne S Mascarella, Robert N Atkinson, Ivy F Carroll
    Abstract:

    Abstract The synthesis of conformationally locked analogs of Epibatidine are described in which the key step is an intramolecular reductive palladium-catalyzed Heck-type coupling.

  • synthesis nicotinic acetylcholine receptor binding and antinociceptive properties of 2 exo 2 2 3 disubstituted 5 pyridinyl 7 azabicyclo 2 2 1 heptanes Epibatidine analogues
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Ivy F Carroll, M. Imad Damaj, Hernan A Navarro, Lawrence E Brieaddy, Philip Abraham, Billy R. Martin
    Abstract:

    A number of 2‘,3‘-disubstituted Epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2‘- and the 3‘-positions showed affinities at the nAChR similar to Epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3‘-Amino-2‘-chloro-5‘-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an Epibatidine analogue possessing an electron-releasing amino group in the 3‘-position, produced the highest affinity. Compound 2i was also the most selective Epibatidine analogue with a Ki of 0.001 nM at αβ nAChRs, which is 26 times greater than that of Epibatidine, and a αβ/α7 Ki ratio of 14 000, twice that of Epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception...

Billy R. Martin - One of the best experts on this subject based on the ideXlab platform.

  • synthesis of bridged analogs of Epibatidine 3 chloro 5 7 8 9 9a 10 hexahydro 7 10 methanopyrrolo 1 2 b 2 6 naphthyridine and 2 chloro 5 5a 6 7 8 10 hexahydro 5 8 methanopyrrolo 2 1 b 1 7 naphthyridine
    Tetrahedron Letters, 2001
    Co-Authors: Lawrence E Brieaddy, Billy R. Martin, M. Imad Damaj, Hernan A Navarro, Wayne S Mascarella, Robert N Atkinson, Ivy F Carroll
    Abstract:

    Abstract The synthesis of conformationally locked analogs of Epibatidine are described in which the key step is an intramolecular reductive palladium-catalyzed Heck-type coupling.

  • synthesis nicotinic acetylcholine receptor binding and antinociceptive properties of 2 exo 2 2 3 disubstituted 5 pyridinyl 7 azabicyclo 2 2 1 heptanes Epibatidine analogues
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Ivy F Carroll, M. Imad Damaj, Hernan A Navarro, Lawrence E Brieaddy, Philip Abraham, Billy R. Martin
    Abstract:

    A number of 2‘,3‘-disubstituted Epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2‘- and the 3‘-positions showed affinities at the nAChR similar to Epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3‘-Amino-2‘-chloro-5‘-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an Epibatidine analogue possessing an electron-releasing amino group in the 3‘-position, produced the highest affinity. Compound 2i was also the most selective Epibatidine analogue with a Ki of 0.001 nM at αβ nAChRs, which is 26 times greater than that of Epibatidine, and a αβ/α7 Ki ratio of 14 000, twice that of Epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception...

  • synthesis nicotinic acetylcholine receptor binding and antinociceptive properties of 2 exo 2 2 substituted 5 pyridinyl 7 azabicyclo 2 2 1 heptanes Epibatidine analogues
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Ivy F Carroll, M. Imad Damaj, Hernan A Navarro, Lawrence E Brieaddy, Philip Abraham, Jeffrey R Lee, Billy R. Martin
    Abstract:

    A number of 2‘,3‘-disubstituted Epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2‘- and the 3‘-positions showed affinities at the nAChR similar to Epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3‘-Amino-2‘-chloro-5‘-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an Epibatidine analogue possessing an electron-releasing amino group in the 3‘-position, produced the highest affinity. Compound 2i was also the most selective Epibatidine analogue with a Ki of 0.001 nM at αβ nAChRs, which is 26 times greater than that of Epibatidine, and a αβ/α7 Ki ratio of 14 000, twice that of Epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception...

  • pharmacological effects of Epibatidine optical enantiomers
    Brain Research, 1994
    Co-Authors: M. Imad Damaj, K R Creasy, A D Grove, John A Rosecrans, Billy R. Martin
    Abstract:

    The pharmacology of synthetic D- and L-Epibatidine, an alkaloid originally characterized from frog skin, were studied in different behavioral tests in mice and rats. The two enantiomers have potent antinociceptive activity in mice using the tail-flick test, with an ED50 of 6.1 and 6.6 micrograms/kg for L- and D-Epibatidine respectively. Epibatidine enantiomers were 200 x more potent than L-nicotine as an antinociceptive agent in mice after s.c. administration. Their analgesic effect was blocked by mecamylamine but not naloxone, an opiate antagonist. Both D- and L-Epibatidine have high affinity (Ki 54.7 and 55.0 pM, respectively) for [3H]nicotine binding site in rat brain. In addition, they reduced mice locomotor activity and body temperature in a dose-dependent manner. In rats trained with nicotine (0.4 mg/kg), Epibatidine enantiomers engendered nicotine-like responding in a dose-related manner with an ED50 of 1.00 and 0.93 micrograms/kg for D and L, respectively. The discriminative effect of L- and D-Epibatidine in rats was blocked by mecamylamine but not by hexamethonium. As in binding results, there was no significant enantioselectivity for these effects in our study.

M. Imad Damaj - One of the best experts on this subject based on the ideXlab platform.

  • synthesis of bridged analogs of Epibatidine 3 chloro 5 7 8 9 9a 10 hexahydro 7 10 methanopyrrolo 1 2 b 2 6 naphthyridine and 2 chloro 5 5a 6 7 8 10 hexahydro 5 8 methanopyrrolo 2 1 b 1 7 naphthyridine
    Tetrahedron Letters, 2001
    Co-Authors: Lawrence E Brieaddy, Billy R. Martin, M. Imad Damaj, Hernan A Navarro, Wayne S Mascarella, Robert N Atkinson, Ivy F Carroll
    Abstract:

    Abstract The synthesis of conformationally locked analogs of Epibatidine are described in which the key step is an intramolecular reductive palladium-catalyzed Heck-type coupling.

  • synthesis nicotinic acetylcholine receptor binding and antinociceptive properties of 2 exo 2 2 3 disubstituted 5 pyridinyl 7 azabicyclo 2 2 1 heptanes Epibatidine analogues
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Ivy F Carroll, M. Imad Damaj, Hernan A Navarro, Lawrence E Brieaddy, Philip Abraham, Billy R. Martin
    Abstract:

    A number of 2‘,3‘-disubstituted Epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2‘- and the 3‘-positions showed affinities at the nAChR similar to Epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3‘-Amino-2‘-chloro-5‘-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an Epibatidine analogue possessing an electron-releasing amino group in the 3‘-position, produced the highest affinity. Compound 2i was also the most selective Epibatidine analogue with a Ki of 0.001 nM at αβ nAChRs, which is 26 times greater than that of Epibatidine, and a αβ/α7 Ki ratio of 14 000, twice that of Epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception...

  • synthesis nicotinic acetylcholine receptor binding and antinociceptive properties of 2 exo 2 2 substituted 5 pyridinyl 7 azabicyclo 2 2 1 heptanes Epibatidine analogues
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Ivy F Carroll, M. Imad Damaj, Hernan A Navarro, Lawrence E Brieaddy, Philip Abraham, Jeffrey R Lee, Billy R. Martin
    Abstract:

    A number of 2‘,3‘-disubstituted Epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2‘- and the 3‘-positions showed affinities at the nAChR similar to Epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3‘-Amino-2‘-chloro-5‘-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an Epibatidine analogue possessing an electron-releasing amino group in the 3‘-position, produced the highest affinity. Compound 2i was also the most selective Epibatidine analogue with a Ki of 0.001 nM at αβ nAChRs, which is 26 times greater than that of Epibatidine, and a αβ/α7 Ki ratio of 14 000, twice that of Epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception...

  • pharmacological effects of Epibatidine optical enantiomers
    Brain Research, 1994
    Co-Authors: M. Imad Damaj, K R Creasy, A D Grove, John A Rosecrans, Billy R. Martin
    Abstract:

    The pharmacology of synthetic D- and L-Epibatidine, an alkaloid originally characterized from frog skin, were studied in different behavioral tests in mice and rats. The two enantiomers have potent antinociceptive activity in mice using the tail-flick test, with an ED50 of 6.1 and 6.6 micrograms/kg for L- and D-Epibatidine respectively. Epibatidine enantiomers were 200 x more potent than L-nicotine as an antinociceptive agent in mice after s.c. administration. Their analgesic effect was blocked by mecamylamine but not naloxone, an opiate antagonist. Both D- and L-Epibatidine have high affinity (Ki 54.7 and 55.0 pM, respectively) for [3H]nicotine binding site in rat brain. In addition, they reduced mice locomotor activity and body temperature in a dose-dependent manner. In rats trained with nicotine (0.4 mg/kg), Epibatidine enantiomers engendered nicotine-like responding in a dose-related manner with an ED50 of 1.00 and 0.93 micrograms/kg for D and L, respectively. The discriminative effect of L- and D-Epibatidine in rats was blocked by mecamylamine but not by hexamethonium. As in binding results, there was no significant enantioselectivity for these effects in our study.

K J Kellar - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and pharmacological characterization of bivalent ligands of Epibatidine at neuronal nicotinic acetylcholine receptors
    Bioorganic & Medicinal Chemistry Letters, 2004
    Co-Authors: Zhiliang Wei, Yingxian Xiao, K J Kellar, Alan P Kozikowski
    Abstract:

    Abstract A series of bivalent ligands 6a – d of Epibatidine were synthesized. All four ligands showed nanomolar binding affinities at six neuronal nicotinic acetylcholine receptor (nAChR) subtypes in competition binding assays. In contrast to Epibatidine, these bivalent ligands are weak partial agonists at the α3β4 nAChR as shown by functional assays.

  • liquid chromatographic studies with immobilized neuronal nicotinic acetylcholine receptor stationary phases effects of receptor subtypes ph and ionic strength on drug receptor interactions
    Journal of Chromatography B: Biomedical Sciences and Applications, 1999
    Co-Authors: Irving W Wainer, Yingxian Xiao, Yanxiao Zhang, K J Kellar
    Abstract:

    Abstract Nicotinic acetylcholine receptor (nAChR) α3-subunits, β4-subunits, α3/β4-subunit combination and α4/β2-subunit combination were immobilized on chromatographic stationary phases and the binding affinities of the different nAChR subtypes were chromatographically evaluated. The observed relative binding affinities of Epibatidine were α4/β2>α3/β4 and Epibatidine did not bind at α3-subunits and β4-subunits. No significant difference in binding affinities was observed on the α4/β2 nAChRs immobilized in immobilized artificial membrane (IAM) particles and those sterically immobilized on Superdex 200 beads. The effects of mobile phase pH and ionic strength on the binding affinities of the α3/β4 nAChRs support were also investigated. The results are consistent with the proposed ligand–nAChR binding model in which a cationic center exists at the binding site.

  • 3h Epibatidine labels nicotinic receptors in rat brain an autoradiographic study
    Journal of Pharmacology and Experimental Therapeutics, 1995
    Co-Authors: David C Perry, K J Kellar
    Abstract:

    Epibatidine, a frog skin alkaloid, is a nicotinic receptor agonist with potent analgesic activity. We used in vitro receptor autoradiographic techniques to map binding sites for [3H]Epibatidine in rat brain, and those for another nicotinic agonist, [3H]cytisine. Both [3H]Epibatidine and [3H]cytisine are excellent radioligands for autoradiography. [3H]Epibatidine in particular binds with very high affinity and extremely low nonspecific binding. In the present study, the distribution of binding was almost identical for both radioligands and closely resembled that of previously published autoradiographic studies with two other nicotinic ligands, [3H]acetylcholine and [3H]nicotine. Brain regions demonstrating the highest levels of [3H]Epibatidine binding included the interpeduncular nucleus, medial habenular nucleus, fasciculus retroflexus, superficial gray layer of the superior colliculus and numerous thalamic nuclei, including the anteroventral, dorsal lateral geniculate and gelatinosus nuclei. Quantitative analysis revealed that [3H]Epibatidine binding was greater than [3H]cytisine binding in several regions. In particular, [3H]Epibatidine clearly labeled the optic nerve, optic chiasm and optic tract, whereas [3H]cytisine binding to these structures did not exceed background levels. Other regions in which [3H]Epibatidine binding was greater than that of [3H]cytisine included the medial habenula, fasciculus retroflexus, olivary pretectal nucleus and superficial gray layer of the superior colliculus. The differences in labeling between these two nicotinic ligands may arise from receptor heterogeneity in brain nicotinic receptors and the ability of [3H]Epibatidine to label more than one subtype of nicotine receptor.

  • characterization of 3h Epibatidine binding to nicotinic cholinergic receptors in rat and human brain
    Molecular Pharmacology, 1995
    Co-Authors: R A Houghtling, Martha I Davilagarcia, K J Kellar
    Abstract:

    Epibatidine is an alkaloid that was first isolated from the skin of the Ecuadoran frog Epipedobates tricolor by Daly et al. [J. Am. Chem. Soc. 102:803-836 (1980)] and was found to have very high affinity for neuronal nicotinic receptors, where it acts as a potent agonist. Here we have measured and characterized the binding of (+/-)(-)[3H]Epibatidine to nicotinic receptors in rat brain. In rat forebrain homogenates, (+/-)(-)[3H]Epibatidine binds to two sites, with apparent affinities of 15 pM and 360 pM. Both of these binding sites have pharmacological profiles consistent with neuronal nicotinic receptors and a similar brain regional distribution. (+/-)(-)[3H]Epibatidine also binds to sites in rat adrenal gland, suggesting that it can label a subtype of nicotinic receptor found in peripheral ganglia as well as the subtype that predominates in brain. In human cerebral cortex as well, (+/-)(-)[3H]Epibatidine binds two sites, one of which appears to have an affinity of < 1 pM. We conclude that (+/-)(-)[3H]Epibatidine should be a very useful new tool for characterizing the properties and regulation of neuronal nicotinic receptors, including those not easily measurable with other radioligands.

Lawrence E Brieaddy - One of the best experts on this subject based on the ideXlab platform.