Discovery of Orally Efficacious Tetracyclic Metabotropic Glutamate Receptor 1 (mGluR1) Antagonists for the Treatment of Chronic Pain

Wu, Wen‐Lian; Burnett, Duane A.; Domalski, Martin S.; Greenlee, William J.; Li, Cheng; Bertorelli, Rosalia; Fredduzzi, Silva; Lozza, Gianluca; Veltri, and Alessio; Reggiani, Angelo

doi:10.1021/jm070590c

Cited by 34 publications

(15 citation statements)

References 21 publications

(24 reference statements)

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“…In the latter case, attaching activating substituents is crucial for further transformations. The introduction of olefinic functionalities such as vinyl or allyl substituents results in valuable starting materials for ring-closing metathesis, [4] epoxidation/dihydroxylation, [5] cyclopropanation, [5b] and polymerization [6] reactions. Cross-coupling reactions, including Hiyama, [7] Kumada, [8] Negishi, [9] Stille, [10] and SuzukiMiyaura [11] reactions, have broadened the scope of applications of substituent modification reactions.…”

Section: Introductionmentioning

confidence: 99%

Calcium‐Mediated Dearomatization, CH Bond Activation, and Allylation of Alkylated and Benzannulated Pyridine Derivatives

Jochmann

Leich

Spaniol

et al. 2011

Chemistry A European J

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A facile and general synthetic pathway for the production of dearomatized, allylated, and C-H bond activated pyridine derivatives is presented. Reaction of the corresponding derivative with the previously reported reagent bis(allyl)calcium, [Ca(C(3)H(5))(2)] (1), cleanly affords the product in high yield. The range of N-heterocyclic compounds studied comprised 2-picoline (2), 4-picoline (3), 2,6-lutidine (4), 4-tert-butylpyridine (5), 2,2'-bipyridine (6), acridine (7), quinoline (8), and isoquinoline (9). Depending on the substitution pattern of the pyridine derivative, either carbometalation or C-H bond activation products are obtained. In the absence of methyl groups ortho or para to the nitrogen atom, carbometalation leads to dearomatized products. C(sp(3))-H bond activation occurs at ortho and para situated methyl groups. Steric shielding of the 4-position in pyridine yields the ring-metalated product through C(sp(2))-H bond activation instead. The isolated compounds [Ca(2-CH(2)-C(5)H(4)N)(2)(THF)] (2b⋅(THF)), [Ca(4-CH(2)-C(5)H(4)N)(2)(THF)(2)] (3b⋅(THF)(2)), [Ca(2-CH(2)-C(5)H(3)N-6-CH(3))(2)(THF)(n)] (4b⋅(THF)(n); n=0, 0.75), [Ca{2-C(5)H(3)N-4-C(CH(3))(3)}(2)(THF)(2)] (5c⋅(THF)(2)), [Ca{4,4'-(C(3)H(5))(2)-(C(10)H(8)N(2))}(THF)] (6a⋅(THF)), [Ca(NC(13) H(9)-9-C(3)H(5))(2)(THF)] (7a⋅(THF)), [Ca(4-C(3) H(5)-C(9) H(7)N)(2)(THF)] (8b⋅(THF)), and [Ca(1-C(3)H(5)-C(9)H(7) N)(2)(THF)(3)] (9a⋅(THF)(3)) have been characterized by NMR spectroscopy and metal analysis. 9a⋅(THF)(4) and 4b⋅(THF)(3) were additionally characterized in the solid state by X-ray diffraction experiments. 4b⋅(THF)(3) shows an aza-allyl coordination mode in the solid state. Based on the results, mechanistic aspects are discussed in the context of previous findings.

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Section: Introductionmentioning

confidence: 99%

Calcium‐Mediated Dearomatization, CH Bond Activation, and Allylation of Alkylated and Benzannulated Pyridine Derivatives

Jochmann

Leich

Spaniol

et al. 2011

Chemistry A European J

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“…Independent yet converging research efforts claim for a crucial involvement of Glu receptors in the mechanism of action of antidepressant [1], antipsychotic [2], antiparkinsonian [3,4] and nociceptive processing [5] drugs. Our continuing interest in this very challenging and promising field of research led us to develop potent and selective ligands for the various members of both ionotropic and metabotropic glutamate receptor families [6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Cysteine-based chiral selectors for the ligand-exchange separation of amino acids☆

Natalini

Sardella

Macchiarulo

et al. 2008

Journal of Chromatography B

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“…Recently developed AMs for mGluR1 (Knoflach et al, 2001;Zheng et al, 2005;Wu et al, 2007), mGluR2 (Johnson et al, 2005), mGluR4 (Stachowicz et al, 2004), and mGluR5 (Lindsley et al, 2004;Roppe et al, 2004;Kinney et al, 2005;Porter et al, 2005;Zhao et al, 2007) have shown in vitro or clinical efficacy for chronic pain, anxiety, Parkinson's disease, and schizophrenia. Several of these series, most notably the PAMs (Ϫ)-PHCCC (mGluR4) (Stachowicz et al, 2004) and CPPHA (mGluR5) (Zhao et al, 2007) demonstrate a surprisingly sensitive structure-activity relationship, because even a slight modification of the parent compound almost invariably results in inactive derivatives.…”

Section: Designing Allosteric Modulatorsmentioning

confidence: 99%

Allosteric Modulators of G Protein-Coupled Receptors: Future Therapeutics for Complex Physiological Disorders

Wang¹,

Martin²,

Brenneman³

et al. 2009

J Pharmacol Exp Ther

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G protein-coupled receptors (GPCRs) are one of the most important classes of proteins in the genome, not only because of their tremendous molecular diversity but because they are the targets of nearly 50% of current pharmacotherapeutics. The majority of these drugs affect GPCR activity by binding to a similar molecular site as the endogenous cognate ligand for the receptor. These "orthosterically" targeted drugs currently dominate the existing pharmacopeia. Over the past two decades, novel opportunities for drug discovery have risen from a greater understanding of the complexity of GPCR signaling. A striking example of this is the appreciation that many GPCRs possess functional allosteric binding sites. Allosteric modulator ligands bind receptor domains topographically distinct from the orthosteric site, altering the biological activity of the orthosteric ligand by changing its binding affinity, functional efficacy, or both. This additional receptor signaling complexity can be embraced and exploited for the next generation of GPCR-targeted therapies. Despite the challenges associated with detecting and quantifying the myriad of possible allosteric effects on GPCR activity, allosteric ligands offer the prospect of engendering a facile stimulus-bias in orthosteric ligand signaling, paving the way for not only receptor-selective but also signaling pathway-selective therapies. Allosteric modulators possess specific advantages when considering the treatment of multifactorial syndromes, such as metabolic diseases or age-related cognitive impairment, because they may not greatly affect neurotransmitter or hormone release patterns, thus maintaining the integrity of complex signaling networks that underlie perception, memory patterns, or neuroendocrinological axes while introducing therapeutically beneficial signal bias.Heptahelical GPCRs are ubiquitously expressed throughout eukaryotic organisms and can account for as much as 3 to 4% of the genome (Foord, 2002). By detecting ligands in the extracellular milieu, they transmit environmental information from outside a cell to the interior. At the same time, changes in the expression of GPCRs or receptor-associated regulatory proteins under varying physiological conditions

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Discovery of Orally Efficacious Tetracyclic Metabotropic Glutamate Receptor 1 (mGluR1) Antagonists for the Treatment of Chronic Pain

Cited by 34 publications

References 21 publications

Calcium‐Mediated Dearomatization, CH Bond Activation, and Allylation of Alkylated and Benzannulated Pyridine Derivatives

Calcium‐Mediated Dearomatization, CH Bond Activation, and Allylation of Alkylated and Benzannulated Pyridine Derivatives

Cysteine-based chiral selectors for the ligand-exchange separation of amino acids☆

Allosteric Modulators of G Protein-Coupled Receptors: Future Therapeutics for Complex Physiological Disorders

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