ABSTRACT
A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10⯵mol/kg compared to control.
Subject(s)
Benzamides/pharmacology , Bridged Bicyclo Compounds/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/chemistry , Dose-Response Relationship, Drug , Humans , Injections, Intravenous , Locomotion/drug effects , Male , Mice , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.
ABSTRACT
A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.
Subject(s)
Analgesics/chemical synthesis , Pain/drug therapy , Peripheral Nervous System Diseases/drug therapy , Pyridazines/chemical synthesis , Quinolines/chemical synthesis , Receptors, Glycine/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Administration, Oral , Alkynes/chemical synthesis , Alkynes/chemistry , Alkynes/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Brain/metabolism , Chronic Disease , Constriction, Pathologic/complications , Male , Pain/etiology , Peripheral Nervous System Diseases/etiology , Pyridazines/chemistry , Pyridazines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Sciatic Nerve/pathology , Structure-Activity RelationshipABSTRACT
Several members of the 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones (2) have been identified as being potent and selective NMDA glycine-site antagonists. Increasing size of the alkyl substituent on the alpha-carbon led to a progressive decrease in binding affinity. Some of these analogues possess improved drug-like properties such as cellular permeability, solubility and oral absorption.
