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Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α₄β₂ nicotinic acetylcholine receptor ligands

(2014) RSC ADVANCES. 4(5). p.2226-2234
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Abstract
The highly potent natural alkaloid epibatidine remains a source of inspiration in the search for new analgesic drugs. In this paper, we describe an expansion of our previously reported synthesis of epibatidine analogues, and five synthetic alkaloids characterized by a symmetric, 1-substituted 7-azabicyclo[2.2.1]heptane skeleton, were evaluated for their biological activity. Two of these are binding selectively to the alpha(4)beta(2) subtype of the nicotinic acetylcholine receptor. Their K-i values were determined to be 40 and 290 nM. After a favourable evaluation of these compounds' cytotoxicity and metabolic stability, they were submitted to a rat tail flick test. The compounds did not show antinociceptive effects, which may be caused by a combination of insufficient potency and poor brain penetration.
Keywords
PAIN, AGONIST, SCHIZOPHRENIA, EXPRESSION, 4-METHANOPROLINE DERIVATIVES, 2, PARKINSONS-DISEASE, CENTRAL-NERVOUS-SYSTEM, POISON FROG, THERAPEUTIC TARGETS, CHOLINERGIC SYSTEM

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Chicago
Heugebaert, Thomas, Melissa Van Overtveldt, Ann De Blieck, Benjamin Wuyts, Patrick Augustijns, Eugenia Ponce-Gámez, Alicia Rivera, et al. 2014. “Synthesis of 1-substituted Epibatidine Analogues and Their in Vitro and in Vivo Evaluation as Α₄β₂ Nicotinic Acetylcholine Receptor Ligands.” Rsc Advances 4 (5): 2226–2234.
APA
Heugebaert, T., Van Overtveldt, M., De Blieck, A., Wuyts, B., Augustijns, P., Ponce-Gámez, E., Rivera, A., et al. (2014). Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α₄β₂ nicotinic acetylcholine receptor ligands. RSC ADVANCES, 4(5), 2226–2234.
Vancouver
1.
Heugebaert T, Van Overtveldt M, De Blieck A, Wuyts B, Augustijns P, Ponce-Gámez E, et al. Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α₄β₂ nicotinic acetylcholine receptor ligands. RSC ADVANCES. 2014;4(5):2226–34.
MLA
Heugebaert, Thomas, Melissa Van Overtveldt, Ann De Blieck, et al. “Synthesis of 1-substituted Epibatidine Analogues and Their in Vitro and in Vivo Evaluation as Α₄β₂ Nicotinic Acetylcholine Receptor Ligands.” RSC ADVANCES 4.5 (2014): 2226–2234. Print.
@article{4305736,
  abstract     = {The highly potent natural alkaloid epibatidine remains a source of inspiration in the search for new analgesic drugs. In this paper, we describe an expansion of our previously reported synthesis of epibatidine analogues, and five synthetic alkaloids characterized by a symmetric, 1-substituted 7-azabicyclo[2.2.1]heptane skeleton, were evaluated for their biological activity. Two of these are binding selectively to the alpha(4)beta(2) subtype of the nicotinic acetylcholine receptor. Their K-i values were determined to be 40 and 290 nM. After a favourable evaluation of these compounds' cytotoxicity and metabolic stability, they were submitted to a rat tail flick test. The compounds did not show antinociceptive effects, which may be caused by a combination of insufficient potency and poor brain penetration.},
  author       = {Heugebaert, Thomas and Van Overtveldt, Melissa and De Blieck, Ann and Wuyts, Benjamin and Augustijns, Patrick and Ponce-G{\'a}mez, Eugenia and Rivera, Alicia and De Groote, Dominic and Lefebvre, Romain and Wouters, Patrick and Meert, Theo and Devulder, Jacques and Stevens, Christian},
  issn         = {2046-2069},
  journal      = {RSC ADVANCES},
  keyword      = {PAIN,AGONIST,SCHIZOPHRENIA,EXPRESSION,4-METHANOPROLINE DERIVATIVES,2,PARKINSONS-DISEASE,CENTRAL-NERVOUS-SYSTEM,POISON FROG,THERAPEUTIC TARGETS,CHOLINERGIC SYSTEM},
  language     = {eng},
  number       = {5},
  pages        = {2226--2234},
  title        = {Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as \ensuremath{\alpha}\unmatched{2084}\ensuremath{\beta}\unmatched{2082} nicotinic acetylcholine receptor ligands},
  url          = {http://dx.doi.org/10.1039/c3ra44379e},
  volume       = {4},
  year         = {2014},
}

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