Synthesis and pharmacological evaluation of sulfonium analogues of dopamine: nonclassical dopamine agonists.
In order to test whether the nitrogen/ammonium moiety in the dopamine molecule is required for dopaminergic activity, we have synthesized two sulfonium analogues of dopamine and tested them for biological activity in an in vivo and in an in vitro system. These analogues have provided a means of investigating (1) the ability of the sulfonium function to serve as a bioisostere for the dopamine amino group and (2) whether charged molecules have the ability to bind to dopamine receptors. Both sulfonium analogues, 1 and 2, as well as dopamine, when injected directly into the striatum of rats, previously lesioned unilaterally with 6-hydroxydopamine (6-OHDA), produced circling behavior. The potency of the sulfonium analogues was approximately one-tenth that of dopamine. The effects of all three compounds on circling were inhibited by the dopamine antagonist haloperidol. In addition, both sulfonium analogues inhibited the high affinity binding of radiolabeled dopamine to a crude membrane fraction prepared from the striatum. This study suggests that the nitrogen atom found in th dopamine molecule is not essential for dopaminergic activity, since the nitrogen can be replaced by a sulfonium functional group for this activity.
D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013329:Structure-Activity Relationship
D011954:Receptors, Dopamine; C031306:(2-(3,4-dihydroxyphenyl)-2-oxoethyl)dimethylsulfonium; C031305:(2-(3,4-dihydroxyphenyl)ethyl)dimethylsulfonium; D004298:Dopamine