Abstract
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
MeSH terms
-
Animals
-
Anti-Anxiety Agents / chemical synthesis*
-
Anti-Anxiety Agents / pharmacokinetics
-
Anti-Anxiety Agents / pharmacology
-
Anxiety / psychology
-
Biological Availability
-
Brain / metabolism
-
Cell Line
-
Cytoskeletal Proteins / antagonists & inhibitors*
-
Cytoskeletal Proteins / metabolism
-
Drinking / drug effects
-
Haloperidol / analogs & derivatives*
-
Haloperidol / chemical synthesis
-
Haloperidol / pharmacokinetics
-
Haloperidol / pharmacology
-
Humans
-
Ligands
-
Male
-
Motor Activity / drug effects
-
Piperidines / chemical synthesis*
-
Piperidines / pharmacokinetics
-
Piperidines / pharmacology
-
Radioligand Assay
-
Rats
-
Rats, Sprague-Dawley
-
Recombinant Proteins / antagonists & inhibitors
-
Recombinant Proteins / metabolism
-
Social Behavior
Substances
-
Anti-Anxiety Agents
-
Cap1 protein, rat
-
Cytoskeletal Proteins
-
Ligands
-
N-(3-(1-((4-(3,4-difluorophenoxy)phenyl)methyl)(4-piperidyl))-4-methylphenyl)-2-methylpropanamide
-
Piperidines
-
Recombinant Proteins
-
1-(3-(4-chlorobenzoyl)propyl)-4-hydroxy-4-(4-chlorophenyl)piperidine
-
Haloperidol