Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists.
ABSTRACT We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models.
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ABSTRACT: A 3D- QSAR model os Comparative Molecular Field Analysib (CoMFA) of 45 quinoline derivatives as metaborropic glutamate receptor subtype 1 (mGluR1) inhibitors wew investigated. The CoMFA analysis provided a model with q(2) value of 0.827 and r(2) value of 0.990, in which q(2) value of 0.827 and an r(2) value of 0.990, in which the good correlation between the inhibitory activities and the steric and electrostatic molecular field around the analoques was observed. The predictive ability of the models was validated using the set of 12 compounds that were not included in the training set of 33 compounds. These results provided further understanding of the relationship between the structural features of quinolone derivatives and its activities, which should be applicable to design and find new potential mGluR1 inhibitors.Chemical Biology & Drug Design 01/2008; 70(6):511-9. · 2.47 Impact Factor
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ABSTRACT: This Review summarizes the medicinal chemistry found in publications on both orthosteric and allosteric modulators of the metabotropic glutamate receptor 1 (mGlu(1)) from 2005 to the present. The time period covered by the scope of this current review has been particularly rich in mGlu(1)-related publications with numbers quadrupling when compared to the preceding five year period of 2000-2005. Publications in the field peaked in 2007 with over 35 articles appearing in the peer reviewed literature in the course of that year. Given that glutamate is one of the primary excitatory neurotransmitters in the mammalian central nervous system (CNS), it is unsurprising that it acts upon several receptors that are considered to be of potential therapeutic interest for many indications. Orthosteric and allosteric modulation of the receptor is possible, with a logical extrapolation to the chemotypes used for each strategy. The last five years of publications have yielded many mGlu(1) selective antagonist chemotypyes, most of which have shown efficacy in pain in vivo models. However, the primary impact of these compounds has been to highlight the mechanistic safety risks of mGlu(1) antagonism, independent of chemotype. As a review in medicinal chemistry, the primary focus of this paper will be on the design and, to a lesser degree, synthetic strategies for the delivery of subtype selective, CNS penetrant, druglike compounds through a "medchem" program, targeting modulators of the mGlu(1) receptor.ACS Chemical Neuroscience 08/2011; 2(8):394-401. · 3.87 Impact Factor
- Journal of Heterocyclic Chemistry 05/2009; 46(3):459 - 464. · 1.22 Impact Factor