The differential activities of R (+)- and S(-)-zacopride as 5-HT3 receptor antagonists.
R(+)- and S(-)-zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-)isomer was more potent than the R(+)isomer to antagonise the hyperactivity induced by the injection of amphetamine or the infusion of dopamine into the nucleus accumbens in the rat. In contrast, the R(+)isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [3H]acetylcholine release in slices of the rat entorhinal cortex. In binding assays, [3H]S(-)-zacopride and [3H]R(+)-zacopride labelled homogenous populations of high-affinity binding sites in the rat entorhinal cortex, R(+)-zacopride compete for a further 10 to 20% of the binding of [3H]R(+)/S(-)-zacopride or [3H]R(+)-zacopride in excess of that competed for by (S)(-)-zacopride. It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition sites to mediate their effects.
Barnes
J M
JM
Postgraduate Studies in Pharmacology, School of Pharmacy, University of Bradford, West Yorkshire, UK.
Barnes
N M
NM
Costall
B
B
Domeney
A M
AM
Johnson
D N
DN
Kelly
M E
ME
Munson
H R
HR
Naylor
R J
RJ
Young
R
R
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002143:Callitrichinae; D003913:Dextroamphetamine / Q000037:antagonists & inhibitors; D004298:Dopamine / Q000494:pharmacology; D005260:Female; D006185:Habituation, Psychophysiologic; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012919:Social Behavior; D013237:Stereoisomerism; D013238:Stereotaxic Techniques
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C055971:zacopride; D003913:Dextroamphetamine; D004298:Dopamine