Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2-<i>exo</i>-2-(2‘-Substituted 5‘-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine Analogues

Carroll, F. Ivy; Liang, Feng; Navarro, Hernán A.; Brieaddy, Lawrence E.; Abraham, Philip; Damaj, M. Imad; Martin, Billy R.

doi:10.1021/jm0100178

Cited by 83 publications

(91 citation statements)

References 21 publications

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“…Seven racemic analogs of epibatidine, with substitutions at the 2Ј position of the pyridine ring, were synthesized as described previously (Carroll et al, 2001). The structures of epibatidine and the analogs are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Norchloro-epibatidine (NEP), fluoro-norchloro-epibatidine (NFEP), bromo-norchloro-epibatidine (NBEP), amino-norchloro-epibatidine (NNEP), hydroxy-norchloro-epibatidine (NOHEP), dimethylamino-norchloro-epibatidine (NDMNEP), and trifluoromethanesulfonate-norchloro-epibatidine (NTEP) were synthesized as described previously (Carroll et al, 2001). All analogs are racemic.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

Avalos¹,

Parker²,

Maddox³

et al. 2002

J Pharmacol Exp Ther

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2Ј-Pyridine ring substituted analogs of epibatidine were assessed for equilibrium binding affinity, functional potency, and efficacy at rat neuronal nicotinic receptors expressed in Xenopus oocytes. Binding affinities were determined in membrane homogenates from oocytes expressing ␣2␤2, ␣2␤4, ␣3␤2, ␣3␤4, ␣4␤2, or ␣4␤4. Efficacy (relative to acetylcholine) and potency were measured electrophysiologically with oocytes expressing ␣3␤4, ␣4␤2, and ␣4␤4. Hydroxy, dimethylamino, and trifluoromethanesulfonate analogs had affinities too low for accurate measurement. The bromo analog had affinities 4-to 55-fold greater at ␤2 than at ␤4-containing receptors, modestly greater efficacy at ␣4␤4 than at ␣4␤2, and 5-to 10-fold greater potency at a4␤4 than at ␣3␤4 or ␣4␤2. The fluoro analog displayed affinities 52-to 875-fold greater at ␤2-than at ␤4-containing receptors, efficacy at ␣4␤4 receptors 3-fold greater than at ␣4␤2 and ␣3␤4, and was equipotent at all receptors tested. The norchloro analog showed affinities 114-to 3500-fold greater at ␤2-than at ␤4-containing receptors, 2-fold greater efficacy at ␣4␤2 and ␣4␤4 than at ␣3␤4, and 4-to 5-fold greater potency at ␣4␤4 and ␣3␤4 than at ␣4␤2. The amino analog displayed affinities 10-to 115-fold greater at ␤2-than at ␤4-containing receptors, 3-fold greater efficacy at ␣3␤4 than at ␣4␤2, and 2-to 4-fold greater potency at ␣3␤4 and ␣4␤4 than at ␣4␤2. Although these compounds displayed a variety of differences in affinity, efficacy, and potency, with one exception (binding affinity and functional potency at ␣4␤4 receptors) there were no significant correlations among these properties.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

Avalos¹,

Parker²,

Maddox³

et al. 2002

J Pharmacol Exp Ther

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“…[24][25][26] Nevertheless, epibatidine is a reference compound for all investigations on nAChRs and a model structure for the design of novel, high affinity and subtype-selective nAChR ligands. Epibatidine-related derivatives have been synthesized by varying the heteroaryl moiety, [27][28][29] or functionalizing and expanding the alicyclic skeleton, [30][31][32][33] or modifying the substituent and/or the position of the epimino nitrogen atom. 34,35 In the light of the above discussed evidences we designed a group of novel compounds in which the two structural elements featuring epibatidine (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…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. 28,37,38 This paper reports the synthesis of compounds 3-5 and the evaluation of their binding affinity at α4β2 and α7 nAChR subtypes. The present results represent a further application of the cycloaddition strategy to the synthesis of biologically active heterocycles, which has characterized our research in the recent years with a focus on chiral ∆ 2 -isoxazoline derivatives selectively acting at the different glutamic acid receptors and transporters.…”

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

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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.

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“…23 These experimental conditions allowed reduction of the reaction time (from 30 to 1.5 h) and improvement of the yield of the Diels-Alder adduct 15 (from 60% to 85%). Subsequently, we prepared the known trifluoromethanesulfonate 11 24 in 62% isolated yield by treatment of ketone 16…”

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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

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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 ...

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Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2-exo-2-(2‘-Substituted 5‘-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine Analogues

Cited by 83 publications

References 21 publications

Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

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

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

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