Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 19; pp. 5340 - 5344
• Main Authors: Ágai-Csongor, Éva, Nógrádi, Katalin, Galambos, János, Vágó, István, Bielik, Attila, Magdó, Ildikó, Ignácz-Szendrei, Györgyi, Keserű, György Miklós, Greiner, István, Laszlovszky, István, Béla Kiss, Éva Schmidt, Judit Laszy, Katalin Sághy, Gyertyán, István, Zájer-Balázs, Mária, Gémesi, Larisza, Domány, György
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-10-2007; Elsevier
• Subjects: Animals; Antipsychotic; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacology; Apomorphine - pharmacology; Arylsulfonamides; Avoidance Learning - drug effects; Binding, Competitive - drug effects; Biological and medical sciences; Biological Availability; Brain - metabolism; Catalepsy - chemically induced; Catecholaminergic system; Cognition - drug effects; Cognition enhancer; Dopamine D3 and D2 ligands; Humans; Indicators and Reagents; Male; Maze Learning - drug effects; Medical sciences; Memory Disorders - chemically induced; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Quantitative Structure-Activity Relationship; Rats; Rats, Wistar; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - metabolism; Stereotyped Behavior - drug effects; Sulfonamides - chemical synthesis; Sulfonamides - metabolism; Sulfonamides - pharmacology; Antipsychotic; Arylsulfonamides; Dopamine D3 and D2 ligands; Cognition enhancer; Nitrile; Rat; Nitrogen heterocycle; Psychotropic; Cognition; D3 Dopamine receptor; Structure activity relation; Benzonitrile derivatives; Antagonist; Chemical synthesis; Human; Sulfonamide; CNS stimulant; Rodentia; Benzene derivatives; Oral administration; Bioavailability; In vitro; In vivo; Vertebrata; Mammalia; D2 Dopamine receptor; Animal; Affinity; Piperazine derivatives; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.08.015

Novel arylsulfonamides were identified as high-affinity dopamine D3 and D2 receptor ligands. Some derivatives were found to be active in antipsychotic tests in vivo.
A novel series of arylsulfonamides was prepared either by automated parallel or by traditional solution-phase synthesis. Several members of this compound library were identified as high-affinity dopamine D3 and D2 receptor ligands. The most interesting representative, compound
2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile.