Antidopaminergic effects of the stereoisomers of N-[(1-alkyl-2- pyrrolidinyl)methyl]-5-sulfamoylbenzamides and -2,3-dihydrobenzofuran-7-carboxamides.
The stereoisomers of some N-[(1-alkyl-2-pyrrolidinyl)methyl]-5- sulfaoylbenzamides (3-8) and -2,3-dihydrobenzofuran-7-carboxamides (9-18) were prepared to compare their dopamine D2 receptor binding affinities (in vitro) and inhibitory effects on apomorphine-induced hyperactivity (in vivo). In the 1-ethyl substituted compounds of the two series, the stereoisomers with S absolute configuration at the 2-position of the pyrrolidine moiety (S enantiomer 3 and 2S diastereomers 9 and 10) were more potent in both of the above activities than those with R absolute configuration (R enantiomer 4 and 2R diastereomers 11 and 12, respectively), whereas the R enantiomer (8) was more potent than the S enantiomer (7) in the 1-n-hexyl-substituted-benzamides and the 2R diastereomers (15, 16, and 18) were more potent than the 2S diastereomers (13, 14, and 17) in the 1-n-butyl- and 1-n-hexyl-2,3-dihydrobenzofuran-7-carboxamides. It was found that the stereospecificity of the compound activities altered from the S configuration to the R configuration as the 1-alkyl side chain became longer in the two series. How these stereoisomers meet the configurational requirements to interact with the dopamine D2 receptors is also discussed.
Murakami
S
S
Central Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
Marubayashi
N
N
Fukuda
T
T
Takehara
S
S
Tahara
T
T
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D018492:Dopamine Antagonists; D007202:Indicators and Reagents; D008968:Molecular Conformation; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D009904:Optical Rotation; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D018492:Dopamine Antagonists; D007202:Indicators and Reagents; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013134:Spiperone