Zacopride and its optical isomers produce stereoselective antagonism of a 2-methylserotonin discriminative stimulus. |
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Authors: | R Young R A Glennon |
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Institution: | Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540. |
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Abstract: | 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. |
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