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Isolated salivary glands from the ixodid tick, Amblyomma hebraeum Koch are stimulated to secrete fluid when exposed to dopamine (DA), the maximum response occurring at 10(-6) M. Spiperone, and a number of other butyrophenone derivatives, although lacking intrinsic activity, are able to potentiate the secretion elicited by supramaximal concentrations of DA; this potentiation by spiperone is evident at concentrations in the femtomolar range. Tranylcypromine, a potent, competitive inhibitor of monoamine oxidase (MAO) in tick salivary gland homogenates, has both intrinsic activity and potentiates DA-induced salivation. The fact that spiperone potentiates ergometrine-induced salivation that the prime mechanism of the butyrophenone effect is not by inhibiting catecholamine catabolism. The results also suggest that the receptor for DA and that for butyrophenones are distinct sites. Droperidol, benperidol and bromperidol, all potent neuroleptic drugs, failed (at 10(-9) M) to potentiate salivation. By contrast, R951, R27275 and R1187 (all at 10(-9) M) were very effective potentiators on the salivary gland system, despite the fact that they lack the basic structural requirements for neuroleptic activity. These results suggest that the butyrophenone site in tick salivary glands is different from butyrophenone binding sites in mammalian CNS.
Polyclonal and monoclonal antibodies to the D2-dopamine receptor antagonist haloperidol were produced by immunization with haloperidol conjugated to bovine serum albumin either through the tertiary hydroxy group of the piperidine ring (halo(OH)-BSA), or through the keto group of the butyrophenone (halo(CO)-BSA). Polyclonal rabbit antisera raised against halo(OH)-BSA exhibited high affinity for [3H]haloperidol. A fraction of these antibodies also bound [3H]spiperone with high affinity. Inhibition of the [3H]spiperone binding by various butyrophenone derivatives displayed a specificity similar to that observed for the inhibition of [3H]spiperone binding to the D2-dopamine receptor. Both monoclonal antibodies raised against halo(CO)-BSA(AG-58) and against halo(OH)-BSA(AC-91) exhibited high binding affinities to haloperidol. Monoclonal antibody AG-58 cross-reacted primarily with butyrophenone derivatives that are closely related to haloperidol in their substitutions on the piperidine ring. On the other hand, monoclonal antibody AC-91 cross-reacted with a wide range of butyrophenones with binding specificities resembling those of the dopamine receptor.
A method has been developed for the simultaneous gas chromatographic determination of propranolol or metoprolol and butyrophenones butyrophenones in human plasma in vitro. The drugs were extracted from plasma by solid-phase extraction. Calibration graphs were linear in the 50-300-ng/mL range. The recovery of the compounds was 80-90%. The sensitivity of the method was adequate for the determination of the drugs at toxic concentrations and at therapeutic levels. It is a simple, rapid, and reproducible method for the simultaneous determination of propranolol or metoprolol and some butyrophenones. The minimum detectable concentration was 50 ng/mL with a flame ionization detector and 10 ng/mL with a mass spectrometer detector.
1 The cataleptic and monoamine-depleting effects of a butyrophenone derivative (4'-fluoro-4-[[4-(p-fluorophenyl)-3-cyclohexen-1-yl]-amino]-butyrophenone hydrochloride, U-32, 802A) were studied in rats and mice and compared with those of tetrabenazine. 2 Catalepsy was evaluated by means of a modified grid test which allowed the repetition of the test in the same animal several times without affecting the results. Both drugs produced a dose-related cataleptic state of similar time course. 3 Like tetrabenazine, U-32, 802A induced a large reduction in the content of 5-hydroxytryptamine, dopamine and noradrenaline in different parts of the brain, with a concomitant elevation in the metabolites 5-hydroxyindol-3-yl acetic acid and homovanillic acid. The time courses of the catalepsy and the reduction in brain monoamines were very similar. 4 The activity of U-32, 802A suggested that the drug, although chemically a butyrophenone, might act primarily at the presynaptic organelle for storage of monoamines in a way similar to tetrabenazine.
A procedure is described for TLC detection and differentiation of the butyrophenone-diphenylbutylpiperidine group and phenothiazine derivatives at the microgram level. A two-dimensional TLC method to separate butyrophenone and diphenylbutylpiperidine compounds is reported. A variety of possible detection reagents were examined. The solvent systems and spray reagents described should be useful for the identification of these drugs in various dosage forms.
A comparison of X-ray powder diffraction patterns, IR spectra, and crystal structures of structurally related compounds belonging to the butyrophenone family has been undertaken to obtain information about the elements of chemical structure which predispose a substance to exhibit polymorphism. Five butyrophenones, differing by the nature of only one substituent, were selected. After crystallization from 15 solvents, it appears that two compounds of the group exhibit more than one crystalline form. An explanation of the absence of polymorphism in the other compounds of the group is proposed and discussed.
A simple and rapid method for isolation of five butyrophenones with Sep-Pak C18 cartridges from human samples, and their wide-bore capillary gas chromatography (GC), are presented. The GC was made by both flame ionization and electron capture detections. The drugs contained in alkaline samples were directly applied to the cartridges and eluted with chloroform/isopropanol (9:1). The recoveries with use of the cartridges were excellent for most drugs in both urine and plasma samples. We can recommend the Sep-Pak C18 cartridges for isolation of butyrophenones because of simplicity and rapidity, and also wide-bore capillary GC because of high sensitivity and low decomposition of drugs during passage through the column.
Platelet shape change responses to 5-hydroxytryptamine were examined in 11 normal subjects and in 78 patients with psychiatric disorders receiving one or more of the following classes of drug: phenothiazine, thioxanthine, butyrophenone, tricyclic antidepressant, benzodiazepine or lithium. Approximately 37% of patients received a single drug, the remainder up to 4 other compounds in addition to the main drug. Platelet shape change induced by 5-hydroxytryptamine (0.25, 2.5 or 25 nmol/ml) was significantly inhibited in patients treated with phenothiazines, thioxanthines and butyrophenones (haloperidol). Tricyclic antidepressants, lithium and benzodiazepines had no effect on 5-hydroxytryptamine-induced shape change. In contrast, a combination of lithium plus chlorpromazine significantly enhanced platelet shape change. Potentiation of noradrenaline-induced aggregation was approximately 50% in normal subjects. This degree of potentiation was not altered in the drug-treated patients although there were quantitative reductions in magnitude of response. Platelet shape change in addition to platelet aggregation may be used as a pharmacological tool to investigate the aetiology of psychiatric disorders and, perhaps eventually, to monitor the clinical efficacy of drug therapy.
Radioiodinated butyrophenone compounds are attracting the interest of those working on dopamine receptor studies; structure-activity relationship study has revealed the ortho position of the p-fluorobutyrophenone moiety as a very plausible iodination site. Various synthesized butyrophenones iodinated at the ortho position of p-fluorobutyrophenone moiety, 2'-iodohaloperidol (2'-IHP), 2'-iodotrifluperidol (2'-ITP) and 2'-iodospiperone (2'-ISP) were tested for their abilities to inhibit 3H-spiperone (SP) binding for the dopamine (D-2) receptor, together with reference compounds (SP, haloperidol(HP) and 4-iodospiperone (4-ISP]. The order of binding affinity of the tested compounds was SP greater than 2'-ISP greater than HP greater than 4-ISP greater than 2'-IHP greater than 2'-ITP. Whereas, the serotonin (S-2) receptor binding affinity of SP and its iodinated analogues were in the order of SP much greater than 4-ISP greater than 2'-ISP. Furthermore, in the saturation binding study using the striatal membrane preparations, the 2'-ISP displayed a KD of 0.25 nM with maximum number of binding site Bmax of 210 fmol/mg protein. These data indicated the 2'-ISP as holding high affinity for dopamine receptors and a low affinity for serotonin receptors. Thus, the 125I-2'-ISP was a very potent radioligand for in vitro dopamine (D-2) receptor studies, and 123I-2'-ISP holds very promising characteristics as for in vivo dopamine receptor studies, as well.
Positive-ion electron-impact (EI), positive-ion chemical ionization (CI) and medium-pressure negative-ion CI mass spectra of ten butyrophenones are presented. Low-pressure (0.01 Torr) negative CI spectra are also presented for some compounds. In the positive EI mode, a peak at m/z 42, which corresponded to the propyl group, appeared for all compounds; a peak at m/z 123 was also common to all compounds except for the two with a bis(fluorophenyl) group. Molecular ions were generally very small or missing in the positive EI mode. In the positive CI mode, strong [M+H]+ quasi-molecular peaks generally appeared together with [M+C2H5]+ peaks; [M-F]+ peaks appeared in many compounds and [M-OH]+ peaks also appeared for compounds having a hydroxypiperidinyl group. In the negative CI mode with a 1 Torr chamber pressure, their spectra were generally simple with [M-H]- quasi-molecular ions; anions of liberated halogens were not observed except for bromine at this pressure. In the negative CI mode at low pressure (0.01 Torr), some fragment peaks in the lower mass range appeared in addition to the quasi-molecular ions; halogen peaks (m/z 19 or 35) and anions at m/z 95, which corresponded to the fluorophenyl group, appeared in most spectra recorded at this pressure. An procedure for the extraction of butyrophenones from human urine and plasma and their separation by gas chromatography was also developed to serve for their identification in forensic science practice.
The preparation of butyrophenone derivatives of 4-aryl-4-(hydroxymethyl)cyclohex-1-ylamines starting from the corresponding 4-cyano-4-phenylcyclohexan-1-ones is described. Substitution was varied with both rings; both isomers of 4-phenyl-4-(hydroxymethyl)cyclohex-1-ylamine were characterized. Those derivatives which carried p-fluoro substitution on the butyrophenone exhibited hypotensive activity in the rat with diminished CNS activity compared to compounds lacking the hydroxymethyl group. The effect of substitution on the 4-aryl ring is discussed.
Effects of butyrophenone and phenothiazine derivatives on the caudate spindle were examined in gallamine-immobilized cats. Butyrophenone derivatives (haloperidol, trifluperidol and methylperidol; 0.5-8.0 mg/kg i.v.) inhibited the caudate spindle activity in a dose-related manner by 13.5-86.5%. Phenothiazine derivatives (chlorpromazine, perphenazine and trifluoperazine; 0.5-8.0 mg/kg i.v.) inhibited the caudate spindle activity only by 4.0-25.1%. The difference of central action between the two derivatives is discussed.
The butyrophenone melperone (Eunerpan) in mice and rats caused a prominetn inhibition of spontaneous activity, whereas cataleptogenic and apomorphine-antagonistic properties were less pronounced. In rats the sleep-cycle was altered: decrease of wakefulness, increase of slow-wave sleep and a moderate reduction of rapid eye movement-(REM) sleep. In contrast to thioridazine and chlorpromazine the effect lasted only for 4 h, followed by a slight REM rebound. In rabbits melperone caused a decrease of muscle tone and with somewhat higher doses an inhibition of the arousal-reaction. As seen by the computerized spontaneous cortical EEG, dosages below 1 mg/kg caused a shift of the dominant frequency from theta- to delta-rhythm and an increase of power. Therefore the neuropharmacological pattern of the butyrophenone melperone is closely related to those of thioridazine or chlorpromazine, without, however, having their long action.
A general method for the syntheses of no-carrier-added (NCA) 18F-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone is described. These 18F-labeled neuroleptic drugs are synthesized by a multistep synthesis in an overall radiochemical yield of 10-20% at end of bombardment (EOB) in a synthesis time of 90 min from EOB. The sequence involves the synthesis of NCA p-[18F]fluorobenzonitrile from NCA [18F]-fluoride and p-nitrobenzonitrile using the rapidly converted to gamma-chloro-p-[18F]fluorobutyrophenone which is alkylated with appropriate amines to give NCA 18F-labeled benperidol, haloperidol, spiroperidol, and pipamperone. The final product is purified by preparative high performance liquid chromatography (HPLC). The 18F solution used in the synthesis as determined by ion chromatography contains 15.3 +/- 9.0 nmol of stable fluoride. The specific activities of the resulting butyrophenone neuroleptics were determined to be 3 Ci/mumol (at EOB) (range 1-6 Ci/mumol) as determined by radioreceptor assay and HPLC assay.
The anticholinesterase (antiChE) activity of haloperidol, droperidol and trifluperidol was studied by employing dog plasma as a cholinesterase source and changes in arterial blood pressure, elecited by a mixture of acetylcholine (Ach) and dog plasma with or without those drugs, as an indicator of their antiChE activity. When butyrophenones were present in concentrations of 0.5 up to 5 X 10(-4)M in plasma containing Ach the hypotensive effect of the latter was preserved. Such findings provide experimental evidence that butyrophenones may exert antiChE activity.
A gas chromatographic procedure with flame ionization detection for the simultaneous determination of diisopyramide and butyrophenones in plasma was developed and evaluated. The quantitative analysis of diisopyramide and butyrophenones (BTPs) was performed in gas chromatograph equipped with packed column (glass column packed with 3% of phenylmethyl silicone-20% ph.), with previous Solid Phase Extraction (SPE) of drugs in C18 minicolumns. For all the drugs considered the accuracy of the proposed method has been evaluated through the recovery test which fell in the range 93-99%, once the absence of matrix interferences has been verified. The precision, expressed as coefficient of variation (CV%), has been of the order of 4%. A 15 m x 0.32 mm i.d. crosslinked, 5% phenylmethyl silicone-coated fused-silica column was also quantitatively utilized and samples were injected using the on-column mode.