Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients.
The bicyclic compound Z-1-(4-bromophenyl)-1-(3-pyridyl)-3-dimethylaminopropen (zimelidine) has a pronounced inhibitory effect on neuronal 5-hydroxytryptamine (5-HT) uptake in animals. Zimelidine was given to 6 depressed patients in doses ranging between 25 and 150 mg twice daily for about 3 wk. To get an objective assessment of its pharmacologic effects, the following variables were monitored: (1) plasma levels of parent compound and its desmethylated metabolite; (2) the 5-HT and norepinephrine (NE) uptake inhibiting activity in vitro of plasma drawn from the patients; and (3) the concentrations of the main metabolites of serotonin (5-HT), tryptamine, NE, and dopamine in cerebrospinal fluid (CSF), i.e., 5-hydroxyindoleacetic acid (5-HIAA), indoleacetic acid (IAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and homovanillic acid (HVA), respectively. Plasma from the patients markedly inhibited 5-HT uptake compared to NE uptake. The inhibitory effect of 5-HT uptake and the plasma concentration of the desmethylated metabolite correlated significantly. The 5-HIAA levels in CSF decreased markedly in 4 patients while the IAA levels increased. The levels of HMPG also decreased significantly, but less so than the 5-HIAA levels. The effects on HVA were inconsistent. Zimelidine appears to be a selective inhibitor of 5-HT uptake in central monoamine neurons and is therefore an interesting pharmacologic tool in future central nervous system (CNS) research.
D000818:Animals; D001679:Biogenic Amines / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001969:Bromobenzenes / Q000378:metabolism* / Q000494:pharmacology; D003640:Dealkylation; D003863:Depression / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D011437:Propylamines / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D011619:Psychotropic Drugs / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D013997:Time Factors
D001679:Biogenic Amines; D001969:Bromobenzenes; D011437:Propylamines; D011619:Psychotropic Drugs; D011725:Pyridines; D012701:Serotonin; D009638:Norepinephrine