The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine as a novel, nonpeptide substance P antagonist

Lowe, John; Drozda, Susan E.; Snider, R. Michael; Longo, Kelly P.; Zorn, Stevin H.; Morrone, Jean; Jackson, Elisa R.; McLean, Stafford; Bryce, Dianne K.

doi:10.1021/jm00092a009

Cited by 116 publications

(61 citation statements)

References 3 publications

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“…13 An alternative conformation seen in X-ray crystal structures and solution conformations of some antagonists has the aromatic rings in the parallel or stacked orientation 13,35-37 that was eliminated in our Constrained Search analyses. This conformation has also been proposed as the bound conformation of these ligands.…”

Section: Resultsmentioning

confidence: 99%

Derivation of a Three-Dimensional Pharmacophore Model of Substance P Antagonists Bound to the Neurokinin-1 Receptor

et al. 1998

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Constrained systematic search was used in an exhaustive conformational analysis of a structurally diverse set of substance P (SP) antagonists to identify a unique hypothesis for their bound conformation at the neurokinin-1 receptor. In this conformation, two aromatic groups essential for high affinity adopt a perpendicular or edge-on arrangement. This pharmacophore hypothesis for the receptor-bound conformation was used in a comparative molecular field analysis (CoMFA) of an expanded set of SP antagonists, and the predictive ability of the resulting three-dimensional quantitative structure-activity relationship (3D-QSAR) was evaluated against a test set of SP antagonists different from those in the training set. This CoMFA model based on the Constrained Search alignment yielded significant cross-validated, conventional, and predictive r2 values equal to 0.70, 0.93, and 0.82, respectively. For comparison, the SP antagonists were forced into an alternative poorer alignment in which the two aromatic rings were parallel and then subjected to a CoMFA analysis. Both the parallel and perpendicular arrangements of the aromatic rings are seen in X-ray structures of SP antagonists and have been proposed as candidates for the receptor-bound conformation. The parallel (or stacked) conformation yielded a poorer correlation with a cross-validated r2 = 0.57, a conventional r2 = 0.90, and a predictive r2 = 0.78. Our results indicate that although both alignments could generate a reasonable CoMFA correlation, the stacked conformation is unlikely to be the receptor-bound conformation, as the covalent structure of the antagonists precludes a common geometry in which the aromatic rings are stacked.

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Section: Resultsmentioning

confidence: 99%

Derivation of a Three-Dimensional Pharmacophore Model of Substance P Antagonists Bound to the Neurokinin-1 Receptor

et al. 1998

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“…To further elucidate the role of the NK1-receptor system in the regulation of consumption of natural reinforcers and ethanol, we evaluated the efficacy of a clinically safe and selective NK1-receptor antagonist, ezlopitant (CJ-11,974) [38], [39] to decrease sucrose and ethanol consumption and seeking. Ezlopitant has previously been investigated in clinical trials as a potential therapy for pain, chemotherapy-induced emesis and irritable bowel syndrome [40], [41].…”

Section: Introductionmentioning

confidence: 99%

The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol

et al. 2010

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BackgroundThe current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer ‘liked’ are still intensely ‘wanted’ [7], . The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown.Methodology/Principal FindingsWe sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974), in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl) solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption.Conclusions/SignificanceThe present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers.

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“…Studies of the available X-ray crystallographic data, and molecular modeling of the Pfizer NK 1 antagonists, have led to postulation of the existence of an intramolecular p-p interaction between the pendant aromatic moieties [57][58][59][60][61]. In selecting the heterocyclic templates for investigation, a primary objective was that a p-p interaction between the indole and bis(trifluoromethyl)phenyl rings should be potentially accessible.…”

Section: Bioisosteric Replacements In Nk 1 Receptor Antagonistmentioning

confidence: 99%

Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

Perruccio

2013

Methods and Principles in Medicinal Chemistry

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The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine as a novel, nonpeptide substance P antagonist

Cited by 116 publications

References 3 publications

Derivation of a Three-Dimensional Pharmacophore Model of Substance P Antagonists Bound to the Neurokinin-1 Receptor

Derivation of a Three-Dimensional Pharmacophore Model of Substance P Antagonists Bound to the Neurokinin-1 Receptor

The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol

Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

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