Synthesis and D2 dopaminergic activity of pyrrolidinium, tetrahydrothiophenium, and tetrahydrothiophene analogues of sulpiride.
All of the existing dopamine receptor models recognize the amine nitrogen of agonist and antagonist drugs as playing a crucial role in receptor interactions. However, there has been some controversy as to which molecular form of the amine, charged or uncharged, is most important in these interactions. We have synthesized and examined the biological activity of permanently charged and permanently uncharged analogues of the dopaminergic antagonist, sulpiride. Sulpiride and the permanently charged pyrrolidinium (6,7) and tetrahydrothiophenium (9) analogues were able to antagonize the inhibitory effect of apomorphine on the K+-induced release of [3H]acetylcholine from striatal slices. In contrast, the permanently uncharged tetrahydrothiophene analogue 8 was inactive at concentrations up to 100 microM. Additionally, both sulpiride and the tetrahydrothiophenium analogue were able to displace [3H]spiperone from D2 binding sites, while the tetrahydrothiophene analogue was unable to produce any significant displacement. These results are consistent with our previous observations on permanently charged chlorpromazine analogues and provide further evidence that dopaminergic antagonists bind in their charged molecular forms to anionic sites on the D2 receptor.
Harrold
M W
MW
Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus 43210.
Wallace
R A
RA
Farooqui
T
T
Wallace
L J
LJ
Uretsky
N
N
Miller
D D
DD
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists; D011188:Potassium / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
D018492:Dopamine Antagonists; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013876:Thiophenes; D013134:Spiperone; D013469:Sulpiride; D001058:Apomorphine; D000109:Acetylcholine; D011188:Potassium