ABSTRACT
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 µM). Compound 6s demonstrated free-plasma exposures above the IC50 (â¼50×) with a brain-to-plasma ratio of â¼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
Subject(s)
Cognition/drug effects , Cyclopropanes/chemical synthesis , Histamine H3 Antagonists/chemical synthesis , Piperazines/chemical synthesis , Receptors, Histamine H3/metabolism , Spiro Compounds/chemical synthesis , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Azetidines/pharmacology , CHO Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Dogs , Histamine H3 Antagonists/pharmacokinetics , Histamine H3 Antagonists/pharmacology , Humans , Learning/drug effects , Madin Darby Canine Kidney Cells , Male , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperazines/pharmacokinetics , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Piperidines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/genetics , Recognition, Psychology/drug effects , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , 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.
