Flupenthixol effects, adenylate cyclase

Thioxanthenes lack the ring nitrogen of phenothiazine, and the side chain is attached by a double bond. In all cases, the cis isomer (relative to the substituted phenyl ring) is more active. Electron-attracting substituents seem to have a cumulative effect. For instance, pifluthixol (4.89), with a fluorine and a trifluoromethyl substituent, is 5-10 times more potent than its parent flupenthixol (4.90), and has an inhibitory effect (IC50 = 9.7 X 10 ° M) on the DA-sensitive adenylate cyclase of the striatum. 

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). 

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. 

Geisler A, Klysner R. Combined effect of litiiium and flupenthixol on striatal adenylate cyclase. Lancet( 911) i, 430-1. 

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