ABSTRACT
The synthesis and SAR of tolylamines with 5-HT(6) receptor antagonist activity is presented. The amine, core aromatic, peripheral aromatic, and ether linker moieties of HTS hit 1 were modulated and the effect on potency at 5-HT(6) examined. Tolylpiperidine ether 9h was found to possess desirable pharmacokinetic (PK) properties, and was also shown to enhance cognition in the rat novel object recognition paradigm.
Subject(s)
Amines/chemistry , Receptors, Serotonin/chemistry , Serotonin Receptor Agonists/chemical synthesis , Animals , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Drug Design , Ethers/chemistry , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Rats , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (alpha2-delta-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the alpha2-delta-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.
Subject(s)
Analgesics/therapeutic use , Calcium Channels/metabolism , Pain/drug therapy , Pain/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , Amino Acid Sequence , Animals , Arginine/genetics , Arginine/metabolism , Autoradiography , Base Sequence , Calcium Channels/chemistry , Calcium Channels/genetics , Calcium Channels, N-Type/metabolism , Cell Line , Chlorocebus aethiops , Constriction, Pathologic , Female , Formaldehyde , Ion Channel Gating/drug effects , Male , Mice , Mice, Transgenic , Mutation/genetics , Pain/genetics , Pregabalin , Protein Binding , Protein Subunits/chemistry , Protein Subunits/genetics , Protein Subunits/metabolism , Swine , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/therapeutic useABSTRACT
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
Subject(s)
Benzofurans/chemical synthesis , Benzofurans/therapeutic use , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Neurodegenerative Diseases/drug therapy , Sulfonamides/chemical synthesis , Sulfonamides/therapeutic use , Transaminases/antagonists & inhibitors , Animals , Benzofurans/chemistry , Calcium/antagonists & inhibitors , Calcium/metabolism , Cells, Cultured , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Glutamic Acid/drug effects , Glutamic Acid/metabolism , Humans , In Vitro Techniques , Models, Molecular , Molecular Structure , Neurons/cytology , Neurons/drug effects , Rats , Rats, Inbred Lew , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of heteroaromatic analogs of pregabalin has been identified that possess anticonvulsant activity in the DBA/2 mouse model. The methods of synthesis and preliminary pharmacology are discussed herein.
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Seizures/prevention & control , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Anticonvulsants/chemical synthesis , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , In Vitro Techniques , Mice , Mice, Inbred DBA , Molecular Structure , Pregabalin , Stereoisomerism , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
As part of a program aimed at generating compounds with affinity for the alpha(2)-delta subunit of voltage-gated calcium channels, several novel beta-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the alpha(2)-delta subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood-brain barrier.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemistry , Calcium Channels/drug effects , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclopropanes/chemical synthesis , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/chemical synthesis , Administration, Oral , Amines/chemistry , Amines/pharmacology , Amino Acid Transport System L/metabolism , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Biological Transport, Active , Blood-Brain Barrier/metabolism , CHO Cells , Calcium Channels/metabolism , Cricetinae , Cricetulus , Cyclization , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Gabapentin , In Vitro Techniques , Injections, Intraventricular , Ion Channel Gating , Male , Mice , Mice, Inbred DBA , Nitriles/chemistry , Pregabalin , Protein Subunits/metabolism , Rats , Rats, Sprague-Dawley , Swine , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
During the last decade, molecular cloning has identified several families of multispecific organic ion transporters mediating the renal and hepatic elimination of organic ions. Clinically, these transporters play important roles in the renal tubular secretion and reabsorption of various drugs. They are also in part responsible for the drug pharmacologic responses, drug-drug interactions, and drug nephrotoxicity. This study describes 12 novel isoforms of the rat kidney organic anion transporter rOAT-K. These isoforms are spliced variants of the same gene arising from alternative splicing of six regions defined as A-F. The two previously reported isoforms rOAT-K1 and rOAT-K2 were also found to be spliced variants of this gene. The open reading frames of the 12 isoforms encode a range of 352-670 amino acid proteins. Tissue distribution studies showed that the majority of the isoforms are kidney- and liver-specific.
