ABSTRACT
Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
Subject(s)
Drug Design , Morpholines/chemical synthesis , Morpholines/pharmacology , Norepinephrine/metabolism , Serotonin/metabolism , Cells, Cultured , Humans , Liver/drug effects , Liver/metabolism , Molecular Structure , Morpholines/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
It has been hypothesized that peripherally restricted NMDA receptor antagonists may be effective analgesics for osteoarthritis pain. A class of novel quinoxalinedione atropisomers, first discovered for an NMDA receptor antagonist program for the treatment of stroke, was evaluated and further optimized with the goal of finding peripherally restricted NMDA receptor antagonists.
Subject(s)
Analgesics/chemistry , Analgesics/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Area Under Curve , Binding Sites , Models, Molecular , Molecular Structure , Pain/drug therapy , Protein Binding , Rats , Structure-Activity Relationship , Sulfonamides/bloodABSTRACT
Photolysis of chromium carbene complexes in the presence of tertiary allylic amines resulted in a zwitterionic aza Cope rearrangement to produce unsaturated lactams in fair yield.
