Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile.
Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig ileum contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson's disease.
Bartoszyk
G D
GD
Department of CNS-Research, Merck KGaA, Darmstadt, Germany. Gerd.Bartoszyk@merck.de
Van Amsterdam
C
C
Greiner
H E
HE
Rautenberg
W
W
Russ
H
H
Seyfried
C A
CA
D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D009930:Organic Chemicals; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine
D000978:Antiparkinson Agents; D008024:Ligands; D009930:Organic Chemicals; D011954:Receptors, Dopamine; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C443959:sarizotan