Zacopride and its optical isomers produce stereoselective antagonism of a 2-methylserotonin discriminative stimulus.
The serotonin 5-HT3 receptor antagonist effects of zacopride and its optical isomers were evaluated in rats trained to discriminate 5.0 mg/kg of 2-methylserotonin (2-Me 5-HT) from saline in a 2-lever operant task. Zacopride and its enantiomers potently antagonized the 2-Me 5-HT stimulus; on the basis of 50% inhibition (ID50) of drug lever responding the order of potency is S(-)-zacopride (ID50 = 0.05 micrograms/kg) greater than (+/-)-zacopride (ID50 = 0.60 micrograms/kg) greater than R(+)-zacopride (ID50 = 1.6 micrograms/kg). The stereoselectivity and potency ratio of zacopride's isomers for antagonizing the 2-Me 5-HT stimulus parallels their previously reported results in binding studies. It is concluded that zacopride's isomers produce antagonism of a 2-Me 5-HT stimulus by stereoselective interaction at 5-HT3 receptors and that stereochemical factors are important in evaluating the stimulus properties of 5-HT3 agents.
Young
R
R
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540.
Glennon
R A
RA
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004193:Discrimination Learning / Q000187:drug effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013237:Stereoisomerism
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; D012701:Serotonin; C045918:2-methyl-5-HT; C055971:zacopride