Abstract
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic beta-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration.
MeSH terms
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Administration, Oral
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Analgesics / chemical synthesis
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Analgesics / pharmacology
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Animals
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Carbolines / chemical synthesis*
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Carbolines / pharmacokinetics*
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Carbolines / therapeutic use
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Disease Models, Animal
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Drug Design
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Excitatory Amino Acid Antagonists / chemical synthesis*
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Excitatory Amino Acid Antagonists / pharmacokinetics
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Excitatory Amino Acid Antagonists / therapeutic use
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Humans
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Inhibitory Concentration 50
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Ligands
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Mice
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Pain / drug therapy*
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Receptors, Metabotropic Glutamate / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Analgesics
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Carbolines
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Excitatory Amino Acid Antagonists
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Ligands
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor type 1