2-(Aryloxymethyl) azacyclic analogues as novel nicotinic acetylcholine receptor (nAChR) ligands

Elliott, Richard L.; Kopecka, Hana; Gunn, David; Lin, Nan‐Horng; Garvey, David S.; Ryther, Keith B.; Holladay, Mark W.; Anderson, David J.; Campbell, John R.; Sullivan, James P.; Buckley, Michael; Gunther, Karen L.; O’Neill, Alyssa B.; Decker, Michael; Arnerić, Stephen P.

doi:10.1016/0960-894x(96)00416-7

Cited by 25 publications

(28 citation statements)

References 29 publications

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“…Compared to the unsubstituted phenyl ether of (S)-N-methylprolinol (S)-1, the meta-hydroxy analogue (S)-4 shows a 40-fold higher α4β2 affinity (1.1 nM K i ) with a good selectivity over the α7 and α3β4 subtypes. Similar α4β2 affinity increase is produced also by the hydroxylation of the phenyl ether of 1-methyl-2-azetidinemethanol: (S)-5 has a 12-fold higher affinity (8.5 nM K i ) than its nonhydroxylated analogue (101 nM K i ), 23 and (S)-5a is 7-fold higher (7.1 nM versus 52 nM K i 23 ). Moreover, functional tests indicate that (S)-4 is a potent full α4β2 agonist (EC 50 = 4.4 μM; 162% maximal efficacy relative to 1 mM ACh) and a partial α3β4 agonist (EC 50 = 9 μM; 85% maximal efficacy relative to 1 mM ACh) showing, however, a functional α4β2 vs α3β4 selectivity sensibly lower than that found in the binding experiments.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 86%

Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists

et al. 2015

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Some unichiral analogues of 2R,2'S-2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective α4β2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high α4β2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High α4β2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known α4β2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the α4β2 and α3β4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of N-methylprolinol are α4β2 full agonists, but only the latter is highly α4β2/α3β4 selective, while potent and selective partial α4β2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 86%

Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists

et al. 2015

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“…A comparison of the QSAR models developed for phenoxymethylpyrrolidines [33] and phenyl pyrrolidines [73], both bearing a phenyl in place of a pyridyl group, pointed out a significant influence of the substituent bulkiness on the binding affinity only for NMPOMP. This can be ascribed to the greater length of the NMPOMP derivatives, which may direct the substituents of the phenyl ring toward more remote and sterically unaccessible receptor regions.…”

Section: Arecolones and Isoarecolonesmentioning

confidence: 99%

“…Many nicotinic ligands, mostly obtained through structural modifications on the pyrrolidine [26][27][28] and pyridine [29][30] rings of nicotine, were examined. Some more recent binding data on aryl-and heteroaryloxymethylcyclic amines [31][32][33] were also taken into account. To gain more valuable information on the receptor topology, positional isomers were analysed separately.…”

Section: Selection Of Ligandsmentioning

confidence: 99%

“…Chemical structures and binding affinities (expressed as pK i ) of the examined nAChR ligands are reported in Tables 1-4. Several different series of neuronal nAChRs ligands were considered, namely nicotine, phenylpyrrolidine, isonicotine and 3-aminomethylpyridine derivatives [26][27][28][29][30] (Table 1), (hetero)aryloxymethylazacyclic derivatives [31][32][33] (Table 2), arecolone and isoarecolone derivatives [34] (Table 3) and nitrogen policyclic derivatives [26, 35-38, 74,75] (Table 4) with various core structures. For inactive ligands (K i > 10,000 nM) a truncated pK i value of 4.50 was used in the derivation of QSAR models to avoid the loss of relevant information.…”

Section: Selection Of Ligandsmentioning

confidence: 99%

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Ligands of Neuronal Nicotinic Acetylcholine Receptor (nAChR): Inferences from the Hansch and 3-D Quantitative Structure-Activity Relationship (QSAR) Models

Nicolotti¹,

Pellegrini-Calace²,

Altomare³

et al. 2002

CMC

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Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. There is evidence to implicate a deficit of nAChRs in the symptomatology of severe neurologic pathologies, such as Alzheimer s and Parkinson s diseases. Reliable three-dimensional structures of nAChRs are not available yet, and this hampers adopting structure-based approaches in designing new ligands. Also pharmacophore models are not reliable enough to be used in ligand-based approaches to drug design and little structure-activity work has been reported so far. This paper deals with structure-activity relationships of a wide series of nicotinic ligands. It provides results from a study of the quantitative structure activity relationships (QSARs) based on literature data of about 270 nicotinic agonists, belonging to various chemical classes. The QSAR study was carried out by using either a classical Hansch approach or a Comparative Molecular Field Analysis (CoMFA). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the factors mainly modulating the receptor affinity, whereas CoMFA allowed us to merge progressively models obtained for each class of congeners into a more general one that showed good cross-validation statistics. The CoMFA coefficient isocontour maps illustrated, at the 3-D level, the most relevant interactions responsible for a high receptor affinity, whereas the robustness of the global three-dimensional QSAR/CoMFA (n = 206, q(2) = 0.749, r(2) = 0.847, s= 0.600) model was supported by the high value of the prediction statistics (r(2)pred = 0.961) and confirmed by the satisfactory predictions of the affinity data of an external set of 18 recently published ligands with chemical structures even quite diverse from those included in the training set.

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“…Substitution of the azetidine ring with methyl as in XXX reduced affinity markedly (Holladay et al, 1998a). There have been reported a few nicotinic agonists, such as chromoproline (Efange et al, 2001), SIB 1553 (Vernier et al, 1999), and XXXI (Elliott et al, 1996), that have an electron-rich phenyl moiety in place of the pyridyl ring. All had low to modest affinity for α 4 β 2 receptors.…”

Section: Pyridyl Ethersmentioning

confidence: 96%

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

2005

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1. Acetylcholine receptors were initially defined as nicotinic or muscarinic, based on selective activation by two natural products, nicotine and muscarine. Several further nicotinic agonists have been discovered from natural sources, including cytisine, anatoxin, ferruginine, anabaseine, epibatidine, and epiquinamide. These have provided lead structures for the design of a wide range of synthetic agents. 2. Natural sources have also provided competitive nicotinic antagonists, such as the Erythrina alkaloids, the tubocurarines, and methyllycaconitine. Noncompetitive antagonists, such as the histrionicotoxins, various izidines, decahydroquinolines, spiropyrrolizidine oximes, pseudophrynamines, ibogaine, strychnine, cocaine, and sparteine have come from natural sources. Finally, galanthamine, codeine, and ivermectin represent positive modulators of nicotinic function, derived from natural sources. 3. Clearly, research on acetylcholine receptors and functions has been dependent on key natural products and the synthetic agents that they inspired.

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2-(Aryloxymethyl) azacyclic analogues as novel nicotinic acetylcholine receptor (nAChR) ligands

Cited by 25 publications

References 29 publications

Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists

Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists

Ligands of Neuronal Nicotinic Acetylcholine Receptor (nAChR): Inferences from the Hansch and 3-D Quantitative Structure-Activity Relationship (QSAR) Models

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

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