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1.
Eur J Pharmacol ; 602(1): 66-72, 2009 Jan 05.
Article in English | MEDLINE | ID: mdl-19027732

ABSTRACT

Antidepressant treatment of two or more weeks in rats has been shown to enhance the locomotor-stimulating effects of dopamine D(2)/D(3) receptor agonists. This action has been attributed to an increased sensitivity of postsynaptic dopamine receptors in the nucleus accumbens, thought to represent an essential mechanism by which antidepressants act therapeutically to enhance reward and motivation. We tested whether the melanin-concentrating hormone receptor(1) (MCH(1)) antagonist SNAP 94847, reported to have antidepressant-like activity in several preclinical behavioral models, mimics this key feature of established antidepressants. Locomotor responses to the dopamine D(2)/D(3) agonist quinpirole following acute or chronic administration of fluoxetine (18 mg/kg/day) or SNAP 94847 (20 mg/kg/day) were assessed in habituated Sprague-Dawley rats, as well as BALB/c and CD-1 mice. Rats showed a significant increase in quinpirole-induced locomotor activity following chronic (2 weeks), but not acute (1 h) fluoxetine or SNAP 94847 administration. BALB/c mice treated for 21 days with fluoxetine or SNAP 94847 showed marked increases in quinpirole-induced locomotor activity, with the onset of hyper-locomotion appearing earlier in the time course after SNAP 94847 compared to fluoxetine. Administration of either compound for 7 days was also sufficient to augment the quinpirole response in BALB/c mice. Fluoxetine and SNAP 94847 (21 days) failed to modify quinpirole responses in CD-1 mice, and the compounds were ineffective after acute administration in both mouse strains. This report demonstrates in two rodent species that chronic treatment with an MCH(1) receptor antagonist, as with clinically proven antidepressants, produces sensitization to the locomotor effects of dopamine D(2)/D(3) agonists.


Subject(s)
Antidepressive Agents/pharmacology , Piperidines/pharmacology , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/agonists , Receptors, Somatostatin/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Fluoxetine/pharmacology , Locomotion/drug effects , Locomotion/physiology , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Time Factors
2.
J Med Chem ; 50(16): 3870-82, 2007 Aug 09.
Article in English | MEDLINE | ID: mdl-17668921

ABSTRACT

Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energy metabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders. Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]-propyl}-piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-isobutyramide ((S)-6b) are reported. These compounds were designed to improve the pharmacokinetic properties of the high-throughput screening lead compound 1 (SNAP 7941). The MCH1 receptor antagonists 5m and (S)-6b show reasonable pharmacokinetic profiles (rat bioavailability = 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated the inhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral in vivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose = 0.3 mg/kg.


Subject(s)
Acetamides/chemical synthesis , Anilides/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cytoskeletal Proteins/antagonists & inhibitors , Piperidines/chemical synthesis , Pyrimidines/chemistry , Acetamides/pharmacokinetics , Acetamides/pharmacology , Anilides/pharmacokinetics , Anilides/pharmacology , Animals , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Anxiety/psychology , Biological Availability , Brain/metabolism , Calcium/metabolism , Cell Line , Cytoskeletal Proteins/metabolism , Drinking/drug effects , Humans , Male , Piperidines/pharmacokinetics , Piperidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Social Behavior , Stereoisomerism
3.
J Med Chem ; 50(16): 3883-90, 2007 Aug 09.
Article in English | MEDLINE | ID: mdl-17668922

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.


Subject(s)
Anti-Anxiety Agents/chemical synthesis , Cytoskeletal Proteins/antagonists & inhibitors , Haloperidol/analogs & derivatives , Piperidines/chemical synthesis , Animals , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Anxiety/psychology , Biological Availability , Brain/metabolism , Cell Line , Cytoskeletal Proteins/metabolism , Drinking/drug effects , Haloperidol/chemical synthesis , Haloperidol/pharmacokinetics , Haloperidol/pharmacology , Humans , Ligands , Male , Motor Activity/drug effects , Piperidines/pharmacokinetics , Piperidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Social Behavior
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