Cis-Flupenthixol

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). 

Radiolabelled cis-flupenthixol can be used as a ligand specific for the dopamine receptor linked to adenylyl cyclase in the rat striatum (64). Its affinity for the dopamine receptor in the anterior pituitary has not been measured. (Previously (65) the two categories of dopamine receptors were designated as a-dopaminergic" and P-dopaminergic. This has led to confusion with the a and p adrenoreceptors. The new designations should prevent further confusion.)... 

Josselyn SA, Beninger RJ (1993) Neuropeptide Y intraaccumbens injections produce a place preference that is blocked by cis-flupenthixol. Pharmacol Biochem Behav -46(3) 543 552. 

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... 

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. 

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. 

A Jorgensen. A sensitive and specific radioimmunoassay for cis (z)-flupenthixol in human serum. Life Sci 23 1533, 1978. 

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