Spiroperidol

Spiroperidol, synthesis 230 (Z)/(ii)-Stereochemistry of aromatic diazo compounds 96 ff. 

Trulson, ME., and Ulissey. J.J. Chronic cocaine administration decreases dopamine synthesis rate and increases [ H] spiroperidol binding in rat brain. Brain Res Bull 19 35-38, 1987. 

Peroutka, S.J., and Snyder, S.H. Multiple serotonin receptors Differential binding of [ H]5-hydroxytryptamine, [ HJlysergic acid diethylamide and [ H]spiroperidol. Mol Pharmacol 16 687-699, 1979. 

Welch MJ, Chi DY, Mathias CJ, Kilboum MR, Brodack JW, Katzenel-lenbogen JA. Biodistribution of A-alkyl and TV-fluoroalkyl derivatives of spiroperidol radiopharmaceuticals for PET studies of dopamine receptors. Appl Radiat Isot 1986 13 523-526. 

Peroutka, S. and Snyder, S. H. Multiple serotonin receptors. Differential binding of [3H]-5-hydroxytryptamine, [3H] lysergic acid diethylamide and [3H]-spiroperidol. Mol. Pharmacol. 16 687-699,1979. 

Robertson, H. A. (1982) Chronic phencyclidine, like amphetamine, produces a decrease in (3H)spiroperidol binding in rat striatum. Eur. J. Pharmacol., 78 363-365. 

Peroutka, S. J., and Snyder, S. H. (1980) Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science, 210 88-90. 

The effects of developmental exposure of pyrethroids on the dopaminergic system, which is considered to be related to behavior, were examined in several studies, but inconsistent results were obtained. Administration of deltamethrin between gestation day 6 and 15 induced increase of DOPAC (dopamine metabolite) levels in adult rats [54]. Exposure of fenvalerate on gestation day 18 and during postnatal days 2-5 produced no effect on monoamine levels on postnatal day 21 [55]. Gestational and lactational exposure to fenvalerate decreased and increased 3H-spiroperidol binding in striatum after development, respectively, whereas only lactational exposure of cypermethrin induced increase in 3H-spiroperidol binding [56]. 

In 1990, Roussell-UCLAF published a patent disclosing that the tertiary amine (83) is a kappa antagonist [in vitro receptor binding IC50 kappa = 57 nM, mu = 840 nM, dopamine (spiroperidol) = 10,600 nM] which when given to rats at 20 mg/kg s.c. antagonizes the diuresis and antinociception induced by U-50488 (5 mg/kg p.o.) [102]. It remains to be seen whether this... 

C. Shiue, J.S. Fowler, A.P. Wolf, M. Watanabe, C.D. Arnett, Synthesis and specific activity determination of NCA F-labeled butyrophenone neuroleptics Benperidol, haloperidol, spiroperidol and pipamperone, J. Nucl. Med. 26 (1985) 181-186. 

M.R. Kilboum, M.J. Welch, C.S. Dence, T.J. Tewson, H. Saji, M. Maeda, Carrier-added and no-carrier-added synthesis of [F-18]spiroperidol and [F-18]haloperidol, Int. J. Appl. Radiat. Isot. 35 (1984) 591-598. 

The synthesis of fluorine-18-labelled receptor-based radiopharmaceuticals carried out before 1986 have been reviewed331 and the methods applied for the synthesis of 18F-butyrophenone neuroleptics such as spiroperidol (spiperone), haloperidol have been critically evaluated. The synthesis for preparing 7V-(2-[18F]fluoroethyl)spiperone330 involving the [18F]fluoride ion displacement of a suitable leaving group on the ethyl side chain was found to be particularly good (>50% yield). 

Figure 11.5. Correlation between the average daily dose of various neuroleptics and their affinity for D2 receptors. (l)=promazine (2)=chlorpromazine (3)=thio-ridazine (4)=clozapine (5)=triflupromazine (6)=penfluridol (7)=trifluoperazine (8)=fluphenazine (9)=haloperidol (10)=pimozide (ll)=fluspirilene (12)=benper-idol (13)=spiroperidol (spiperone).

Tissue Ka, yM Dopamine a-Flupenthixol Ki, nM Fluphenazine Spiroperidol Reference... 

Ki for haloperidol. Spiroperidol and haloperidol are of comparable potency in several dopamine-sensitive adenylate cyclase systems. 

Dopaminergic neurons synapse upon the parenchymal cells of the intermediate lobe (IL) of the rat pituitary gland. Dopamine decreases the capacity of the IL cells to synthesize cyclic AMP and inhibits the release of otMSH and other peptides from this tissue. The presence of a D-2 receptor accounts for both of these phenomena. This D-2 dopamine receptor can be studied in a binding assay using [3H]-spiroperidol, a dopamine... 

Figure 6. Binding of [3H]-spiroperidol to cell-free homogenates of the neurointermediate lobe of the rat pituitary gland.

Key A, total ( ) and nonspecific binding (i.e., binding in the presence of 2 nM fluphenazine) (O) was determined in the presence of the indicated concentrations of [3HJ-spiroperidol and B, specifically bound [3H]-spiroperidol (i.e., the difference between total and nonspecific binding) is shown as a function of the concentration of [3H] spiroperidol. Left inset a plot of the data in B according to Rosenthal s method yields an apparent Kd of 0.2 nM and a maximal concentration of specific binding sites of 94.1 fmol/mg protein (this is equivalent to 20.2... 

Figure 7. Competition between [3H]-spiroperidol and dopamine for occupancy of binding sites in the NIL of the rat pituitary gland. The amount of [3H]-spiro-peridol bound to NIL tissue was determined in the presence of 2 fluphenazine (0), 2 (iM fluphenazine and 100 GTP (4) or dopamine (at the indicated concentrations) in the absence (O) or presence (9) of 100 GTP (33).

For each response examined, inhibition of isoproterenol-stimulated cAMP accumulation by intact cells ( ) inhibition of basal release of IR-aMSH by intact cells ( J occupancy of specific [3H]-spiroperidol binding sites in a cell-free homogenate (Q) and inhibition of isoproterenol-stimulated adenylate cyclase activity in a cell-free homogenate (M), the effect achieved with the indicated concentration of apomorphine is expressed as a percentage of the maximal effect of apomorphine (33). 

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). 

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