Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

Romanelli, Maria Novella; Gualtieri, Fulvio

doi:10.1002/med.10037

Cited by 111 publications

(69 citation statements)

References 249 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16) An important aspect of nicotinic drug development is the quest for high subtype-selectivity. 16,17) …”

Section: Subtype Selectivitymentioning

confidence: 99%

Neonicotinoids and Derivatives: Effects in Mammalian Cells and Mice

Tomizawa¹

2004

J. Pestic. Sci.

View full text Add to dashboard Cite

Neonicotinoids are the only major new class of insecticides introduced in the past three decades. They act as selective agonists at the insect nicotinic acetylcholine receptor and are therefore highly toxic towards important insect pests but relatively safe to mammals. However, the excellent selective toxicity may not be evident with their metabolites or analogous compounds. The aim of this paper is to consider the effects of neonicotinoids and derivatives in mammalian cells and mice involving up-regulation of nicotinic receptor levels and activation of the intracellular signal integration cascade elicited by chronic or sustained exposure and analgesic and toxic effects in mice.

show abstract

“…16) An important aspect of nicotinic drug development is the quest for high subtype-selectivity. 16,17) …”

Section: Subtype Selectivitymentioning

confidence: 99%

Neonicotinoids and Derivatives: Effects in Mammalian Cells and Mice

Tomizawa¹

2004

J. Pestic. Sci.

View full text Add to dashboard Cite

show abstract

“…1), a highly toxic alkaloid identified in the skin of the Ecuadorian frog Epipedobates tricolor, 10 has inspired a huge amount of research aimed at designing subtype selective nicotinic agonists. 1,2,9,11,12 Although the pharmacological effects of (À)-2 are mediated by a variety of nAChRs, 13 which preclude any therapeutic potential for epibatidine, the analgesic potency, roughly 100 times higher than that of morphine and 30 times higher than that of nicotine, has been attributed to its high affinity for the a4b2 subtype. Worth mentioning, (À)-2 and (+)-2 are characterized by similar affinities for nAChRs and almost identical ED 50 values in the mouse tail-flick antinociception assay.…”

Section: Introductionmentioning

confidence: 99%

Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes

Rizzi

Dallanoce

Matera

et al. 2008

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

a b s t r a c tRacemic exo-epiboxidine 3, endo-epiboxidine 6, and the two unsaturated epiboxidine-related derivatives 7 and 8 were efficiently prepared taking advantage of a palladium-catalyzed Stille coupling as the key step in the reaction sequence. The target compounds were assayed for their binding affinity at neuronal a4b2 and a7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity a4b2 ligand (K i = 0.4 nM) and, interestingly, evidenced a relevant affinity also for the a7 subtype (K i = 6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (K i = 50 nM for a4b2 and K i = 1.6 lM for a7) evidenced a gain in the a4b2 versus a7 selectivity when compared with the model compound.Ó 2008 Elsevier Ltd. All rights reserved.Neuronal nicotinic acetylcholine receptors (nAChRs) make up a family of pentameric ligand-gated ion channels, which are formed by combinations of alpha and beta subunits 1,2 or exist as homopentamers, in the cases of a7, a8, and a9 receptors, which are inhibited by a-bungarotoxin. 3 To date, nine a (a2-a10) and three b (b2-b4) isoforms have been characterized, though only a relatively small subset of combinations generates functionally and physiologically relevant channels. 4 Nicotinic receptors are widely distributed in the brain, where they primarily modulate the release of other neurotransmitters and, to a lesser extent, mediate synaptic transmission. 5 Neuronal nAChRs, selectively activated by (S)-nicotine 1 (Fig. 1), are involved in various processes such as cognition, learning and memory, cerebral blood flow and metabolism, as well as an array of pathological conditions such as Alzheimer's and Parkinson's diseases, mild cognitive impairment (MCI), schizophrenia, epilepsy, Tourette's syndrome, anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and nicotine addiction.1,2,6,7The heteromeric a4b2 receptors, the most abundant subtype in the mammalian CNS, and the homomeric a7 channels are privileged biological targets in the search for selective nAChR ligands with therapeutic potential. 2,8 As far as the number of nicotinic agonists isolated from natural sources is taken into consideration, 9 (À)-epibatidine 2 (Fig. 1), a highly toxic alkaloid identified in the skin of the Ecuadorian frog Epipedobates tricolor, 10 has inspired a huge amount of research aimed at designing subtype selective nicotinic agonists. 1,2,9,11,12 Although the pharmacological effects of (À)-2 are mediated by a variety of nAChRs, 13 which preclude any therapeutic potential for epibatidine, the analgesic potency, roughly 100 times higher than that of morphine and 30 times higher than that of nicotine, has been attributed to its high affinity for the a4b2 subtype. Worth mentioning, (À)-2 and (+)-2 are characterized by similar affinities for nAChRs and almost identical ED 50 values in the mouse tail-flick antinociception assay. 13d,14,15 Among the synthetic epibatidine-related compounds, (±)-epiboxidine 3 (Fig. 1), in which ...

show abstract

“…The aim of this study was to investigate the effect of the variation of both the epimino-N/pyridine-N distance and the conformational profile on the affinity/selectivity for the nAChR subtypes. Since the chlorine atom located on the pyridine ring makes a minor contribution to the affinity of epibatidine, 36 we decided to synthesize the unsubstituted pyridinyl regioisomers only. Moreover, the novel chiral derivatives 3a-c and 4a-c were prepared as racemates by taking into account the similar receptor binding efficiencies of the epibatidine enantiomers.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel epibatidine-related derivatives through 1,3-dipolar cycloaddition of pyridinenitrile oxides

Dallanoce¹,

Bazza²,

Grazioso³

et al. 2006

Arkivoc

View full text Add to dashboard Cite

The ∆ 2 -isoxazoline derivatives 3a-c and 4a-c, structurally related to epibatidine, and the simplified analogues 5a-c were synthesized by means of a 1,3-dipolar cycloaddition of regioisomeric pyridinenitrile oxides to suitable dipolarophiles. Target compounds were assayed at α4β2 and α7 neuronal acetylcholine receptor (nAChR) subtypes. Competition binding experiments at α4β2 nAChRs showed an overall significant reduction in affinity for the compounds under study in comparison to the reference radioligand [ 3 H]-epibatidine. On the other hand, compounds 3b, 3c, and 4b exhibited a noticeable affinity for the α7 receptors and 3c showed also a slight degree of α7 over α4β2 selectivity.

show abstract

Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

Cited by 111 publications

References 249 publications

Neonicotinoids and Derivatives: Effects in Mammalian Cells and Mice

Neonicotinoids and Derivatives: Effects in Mammalian Cells and Mice

Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes

Synthesis of novel epibatidine-related derivatives through 1,3-dipolar cycloaddition of pyridinenitrile oxides

Contact Info

Product

Resources

About