Dopamine agonists: effects of charged and uncharged analogs of dopamine

Abstract

Dopamine, at physiological pH, may exist as either an uncharged amine or a charged ammonium species. In order to gain insight as to which species is better suited for interaction with the dopamine receptor, we have synthesized dopamine analogues in which the nitrogen atom is replaced with a neutral methyl sulfide, a neutral methyl selenide, a charged dimethylsulfonium iodide, and a charged dimethylselenonium iodide. These analogues were tested for their ability to inhibit the K+-stimulated release of [3H]acetylcholine from striatal slices. At 30 microM concentration, the charged sulfonium and selenonium salts possessed significant agonist activity while the corresponding neutral species were inactive, suggesting that a charged species is optimal for dopamine agonist activity. In addition, the methyl sulfide was converted into the corresponding sulfoxide and sulfone; however, neither of these oxidation products possessed significant activity as dopaminergic agonists.

2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: Potent Non-Nitrogen Inhibitors of Monoamine Transporters

“…Indeed, in 1979 Brownbridge and Chan prepared the 8-oxa analog of cocaine although no biological data were reported for that compound. More recently, Miller et al − explored the substitution of sulfur for nitrogen in their studies on D 2 ligands. They showed that a nitrogen could be replaced by sulfur in these molecules and potency, albeit much diminished, could be maintained.…”

A Three-Step, Gram-Scale Synthesis of Hydroxytyrosol, Hydroxytyrosol Acetate, and 3,4-Dihydroxyphenylglycol

“…The next step concerns the reduction of the carbonyl group; still all the initial attempts, under several conditions, provided complex mixtures. Among the variety of conditions used for the reduction of compound 2 , only the reduction with triethylsilane in the presence of a Lewis acid gave the desired chloro compound 3 [77,78,79,80]. More precisely, of the various Lewis acids and reaction conditions that were tested, the use of a fourfold excess of trifluoroacetic acid or a fivefold excess of boron trifluoride etherate and a twofold excess of triethylsilane derived the desirable catechol 3 in 95% or 92%, respectively.…”

Synthesis and D2 dopaminergic activity of pyrrolidinium, tetrahydrothiophenium, and tetrahydrothiophene analogs of sulpiride

“…2-Methoxy-5-suIfamoylbenzoic Acid (11). Chlorosulfuric acid (50 mL) was cooled to 0 °C in an ice bath, and o-anisic acid (10.0 g, 65.7 mmol) was slowly added in small increments.…”

“…The synthesis of the tetrahydrothiophene analogue of sulpiride was accomplished by three related, but independent, routes. Initially o-anisic acid (10) was converted to 2-methoxy-5-sulfamoylbenzoic acid (11) by sequential chlorosulfonation14 and ammonium displacement (Scheme I). This acid was then activated with ethyl chloroformate,15 and the resulting adduct was reacted in situ with 2,5-dichloroamylamine hydrochloride and triethylamine to afford benzamide 12.…”

“…The question of which molecular species, charged or uncharged, is most important for the binding of dopamine agonists to the dopamine receptor has recently been addressed. 10,11 Studies with permanently charged and permanently uncharged sulfur and selenium analogues of dopamine suggested that the charged, protonated form of dopamine is the molecular species required for maximal activation of the dopamine D2 receptor. In order to determine if dopamine antagonists also require a charged species for maximal activity, our group originally investigated a series of permanently charged and uncharged analogues of chlorpromazine (l).12 Permanently charged ammonium (2) and sulfonium (3) analogues of chlorpromazine retained the ability to both bind and act as antagonists at the dopamine D2 receptor.…”