Dopaminergic antagonists

Phenothiazines are also nonspecific dopaminergic antagonists and are an old family of neuroleptics. However, they are less and less used (fluphenazine, oxa-flumazine, trifluoperazine, triflupromazine). Flupenthixol and isofloxythepine are recent neuroleptics that can be grouped with phenothiazines (Figure 8.29). 

Oloff, S., Mailman, R. B., Tropsha, A. (2005) Application of validated QSAR models of D1 dopaminergic antagonists for database mining. J Med Chem 48, 7322-7332. 

Effects of Dopaminergic Antagonists on Calmodulin-stimulated Phosphodiesterase Activity... 

The stereospecific dopaminergic antagonists (-) and (+) butaclamol and cis- and trans-flupenthixol were of equal potency in their effects on calmodulin-dependent phosphodiesterase activity. This contrasts with the marked difference in the potency of each pair of stereoisomers as dopamine antagonists. It appears unlikely that the calmodulin-dependent phosphodiesterase activity (and by inference calmodulin) plays any role in the actions of dopaminergic antagonists upon the bovine parathyroid gland. 

Effects of dopaminergic antagonists on dopamine-stimulated cAMP accumulation, adenylate cyclase activity, and calmodulin-stimulated phosphodiesterase (PDE) activity in intact bovine parathyroid cells or cellular homogenates. Values for or IC50 are given as uM. NT, not tested. 

Die specificity of the dopamine receptor was further studied with a series of dopaminergic antagonists of well known pharmacological activity. The 30-40% inhibitory effect of 10 nM dopamine was completely reversed by the addition of increasing concentrations of the potent neuroleptics (+)butaclamol (Kp = 1.5 nM) and (-)sulpiride (Kp = 0.5 nM) while their pharmacologically weak enantiomers (-)butaclamol and (+)sulpiride were 86 and 167 times less potent, respectively. The neuroleptics spiroperidol, thioproperazine, domperidone, haloperidol, fluphenazine and pimozide completely reversed the inhibitory effect of dopamine at low Kp values ranging from 0.02 to 0.8 nM (41). 

We end this chapter with a simple commercial synthesis of a drug molecule described as a dopaminergic antagonist. It uses four reactions that you have met conjugate addition of an enolate to acrylonitrile reduction of CN to a primary amine alkylation and reduction of the amide. There is another reaction involved—cyclization to an amide—but this occurs spontaneously. These reactions may be simple but they are important. 

Tardive dyskinesias (TDs) are involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated with long-term dopaminergic antagonist medications. TDs can be differentiated from acute movement disorders that commonly occur in the same patient groups the acute movement disorders resulting from exposure to dopamine antagonists are commonly termed extra-pyramidal syndromes. 

FIGURE 6.19 The passage from pethidine-related opiate analgesics to the dopaminergic antagonist haloperidol. 

FIGURE 16.37 The conjunctive method applied to the design of haloperidol-derived dopaminergic antagonists. 

Conventional therapies include dopaminergic antagonists such as haloperidol and pimozide. Recent evidence indicates that the addition of low-dose nicotine to the regimen significandy reduces the incidence and severity of facial tics, indicating that the use of transcutaneous nicotine as adjunct therapy may improve manifestations of the disorder. 

Dopaminergic antagonists. Starting from the flexible haloperidol molecule, Humber and colleagues designed the rigid (+)-butaclamol that contains three clearly defined stereocentres (Fig. 14.33). The same stereochemical requirements as in (+ )-butaclamol are found in compound Ro 14-8625 prepared by Imhof et al. ... 

---