Antagonist flupenthixol

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). 

Fletcher A, Forster EA, Bill DJ, et al Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HTj receptor antagonist. Behav Brain Res 73 337-353, 1996 Fletcher PJ, Higgins GA Differential effects of ondansetron and alpha-flupenthixol on responding for conditioned reward. Psychopharmacology 134 64-72, 1997 Flood JF, Smith GE, Roberts E Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res 447 269-277, 1988... 

With the typical neuroleptics in wide clinical use (e.g. chlorpromazine, thioridazine, haloperidol, pimozide, flupenthixol and clopenthixol), there would appear to be a correlation between their D2 antagonistic potency and their clinical potency presumably the ability of these drugs to block 5-HT2 receptors to varying extents is also evidence that the serotonergic system is involved in their clinical activity in some way. 

In either the presence or absence of GTP, half-maximal stimulation of enzyme activity is achieved with 3 uM dopamine. Both 6,7-ADTM and epinine (K-methyl dopamine) stimulate adenylate cyclase activity to the same degree as does dopamine (Figure 8). In contrast, apomorphine is a partial agonist eliciting only 30 of the maximal effect of dopamine. The dopamine-stimulated adenylate cyclase activity is selectively blocked by cis-flupenthixol rather than the trans-isomer of this antagonist (JJL). Among the antagonists tested, the order of potency is cis-flupenthixol = fluphenazine > chlorpromazine > haloperidol > trans-flupenthixol (Table I). 

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. 

ADTN and other dopamine agonists mimicked this effect which was antagonized by a- and B-flupenthixol, the a-isomer being 100 times more potent. In a similar way, dopamine caused a rapid 20-30-fold increase in cellular cAMP in dispersed bovine parathyroid cells. The potency of a series of dopaminergic agonists and antagonists on adenylate cyclase activity paralleled the effects of these ligands on CAMP accumulation and parathormone secretion (16). It was concluded that bovine parathyroid cells possess dopamine sites which are involved in the control of parathormone secretion. 

In the appetitive autoshaping paradigm, intra-accumbens infusions of the D1/D2 receptor antagonist alpha-flupenthixol did apparently impair discrimination to a much greater extent in acquisition than performance (DiCiano et al., 2002). 

D-1 (cyclase-linked) Bovine parathyroid Agonist (pM range) partial agonist or antagonist Potent antagonist (nM) or weak agonist (pM) None known as yet cis-Flupenthixol... 

I a- but not p-flupenthixol has antipsychotic activity greater than placebo (only the a isomer is antagonist at D2 receptors) (Fig. 3.2). 

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