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

Abstract

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.

Visualization of Antipsychotic Drug Binding to Living Mesolimbic Neurons Reveals D2 Receptor, Acidotropic, and Lipophilic Components

“…Because antipsychotic drugs are thought to bind to D2 receptors in part via their positively charged amine moieties (Harrold et al ., 1989), antipsychotics should be weak bases . Indeed, all have pK values in the range of 7 .0-9.5 (see references in Table 1), indicating that some antipsychotic molecules will be neutral at physiological pH [or zwitterions forming an internal salt, as is the case for raclopride and will partition across membranes .…”

Applications of Chiral Squaramides: From Asymmetric Organocatalysis to Biologically Active Compounds

“…In 2012, work by Xu and coworkers demonstrated that the chiral tetrahydrothiophene compounds 44-46, which exhibited D2 dopaminergic activity and anti-HIV activity as well, [29] could be synthesized by an efficient method via a bifunctional squaramide C2-catalyzed domino sulfa-Michael/aldol reaction between 1,4-Dithiane-2,5-diol 43 and chalcones in high yields (71-91%) and excellent stereoselectivities (8: 1-20: 1 dr and 84-97% ee values) (Scheme 17). [30,31] Cyclobutane derivatives are significant drug intermediates with higher stability than cyclopropane.…”

Platinum(II) complexes with thiourea derivatives containing oxygen, sulfur or selenium in a heterocyclic ring: computational studies and cytotoxic properties

“…[20]. The final product was prepared by a modified method applied for the preparation of n-butyl isothiocyanate [19]: A mixture of 2-thiolanylmethylamine (1.23 g, 10.5 mmol), triethylamine (1 mL, 0.73 g, 7.2 mmol) and 2 mL of dioxane was chilled to -10°C and treated with Scheme 1 Thiourea ligands used in this study carbon disulfide (0.5 mL, 0.63 g, 8.3 mmol).…”