Synthesis and pharmacological evaluation of sulfonium analogs of dopamine: nonclassical dopamine agonists

Abstract

To test whether the N/ammonium moiety in the dopamine molecule is required for dopaminergic activity, 2 sulfonium analogs of dopamine were synthesized and tested for biological activity in an in vivo and in an in vitro system. These analogs have provided a means of investigating the ability of the sulfonium function to serve as a bioisostere for the dopamine amino group, of observing and the ability of charged molecules to bind to dopamine receptors. Both sulfonium analogs and 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 analogs was approximately 1/10 that of dopamine. The effects of all 3 compounds on circling were inhibited by the dopamine antagonist haloperidol. The sulfonium analogs inhibited the high affinity-binding of radiolabeled dopamine to a crude membrane fraction prepared from the striatum. The N atom found in the dopamine molecule is not essential for dopaminergic activity, as the N can be replaced by a sulfonium functional group for this activity.