Phenyl pyrrolidine analogues as potent nicotinic acetylcholine receptor (nAChR) ligands

Elliott, Richard L.; Ryther, Keith B.; Anderson, David J.; Raszkiewicz, Joanna L.; Campbell, John R.; Sullivan, James P.; Garvey, David S.

doi:10.1016/0960-894x(95)00154-l

Cited by 22 publications

(26 citation statements)

References 23 publications

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“…Ligands 48-65 (Table 1) [73] exhibited binding affinities lower than the corresponding nicotine derivatives. The lead compound 49 showed indeed a pK i value of about 2.5 units lower than nicotine.…”

Section: N-methyl-2-phenylpyrrolidines (Nmpp)mentioning

confidence: 96%

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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Section: N-methyl-2-phenylpyrrolidines (Nmpp)mentioning

confidence: 96%

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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“…Dukat's group also determined that the anisole analog of PMP has very little affinity for α4β2 receptors [c98]. Latli and coworkers [155] very recently described the synthesis and pharmacology of a group of 6-chloropyridyl analogs closely related to PMP [c95 -97]. Interestingly, the azetidinyl analog [c95] binds with about half the affinity of the related pyrrolidinyl analog [c96].…”

Section: Ii4b Class B: Cyclic Hba/π Acyclic Cationmentioning

confidence: 98%

“…Compounds based on elaboration of imidacloprid's imidazolidin-2-imine core have been recently explored by Latli and coworkers [155]. One unique aspect of these compounds is the fact that the positive charge is resonance stabilized over the guanidine nitrogen triad.…”

Section: Ii4b Class B: Cyclic Hba/π Acyclic Cationmentioning

confidence: 98%

Exploring the Nature of Molecular Recognition in Nicotinic Acetylcholine Receptors

Schmitt

2000

CMC

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Nicotinic acetylcholine receptors (nAChRs) are the subject of ever increasing interest because of their presumed involvement in the etiology of numerous clinical disorders. Unfortunately, the absence of atomic-level structural data, as well as the pharmacological complexity of these receptors leaves many fundamental questions unanswered. An understanding of how ligands interact with the receptor and, in-turn, how these interactions lead to pharmacological effect is vital in the advancement of nAChR-based therapeutics. We will first explore physico-chemical themes that are evidenced to be of particular importance in nAChR molecular recognition; these are- pi-cation interaction, conformational entropy and stereochemistry. The second objective of this review is an interpretive encapsulation of the extensive and disparate body of structure-activity data that now exists for nAChRs. Finally, this review will advocate a re-investigation of distance geometry based methods as well as the need for additional approaches in nicotinic receptor pharmacophore generation.

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“…A number of other conformationally constrained analogs had very low affinities (Glennon and Dukat, 2000;Xu et al, 2001;Avenoza et al, 2002Avenoza et al, , 2002. Remarkably, replacement of the pyridyl ring of nicotine with an electron-rich phenyl ring as in methylenedioxyphenylnicotine (IX) did not completely eliminate activity (Elliott et al, 1995), as also could be considered the case for DMPP (Fig. 3).…”

Section: Nicotine-based Nicotinic Agonistsmentioning

confidence: 94%

“…3). Most phenylpyrrolidines have very low affinities for α 4 β 2 receptors (Elliott et al, 1995). Finally, the desnitro analog of the potent nicotinic insecticide imidacloprid, but not imidacloprid itself retained modest affinity for the α 4 β 2 receptor (D' Amour and Casida, 1999;Latli et al, 1999).…”

Section: Nicotine-based Nicotinic Agonistsmentioning

confidence: 98%

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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Phenyl pyrrolidine analogues as potent nicotinic acetylcholine receptor (nAChR) ligands

Cited by 22 publications

References 23 publications

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

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

Exploring the Nature of Molecular Recognition in Nicotinic Acetylcholine Receptors

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

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