Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Butaclamol”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed1984

Computer-assisted video analysis of [3H]spiroperidol binding autoradiographs.

A computer-based video image processing system is described that quantifies the binding of the neuroleptic drug, [3H]spiroperidol, to rat forebrain sections. Adjacent sections were incubated in buffer containing [3H]spiroperidol or [3H]spiroperidol plus 1 microM (+)-butaclamol and exposed to tritium-sensitive film to produce autoradiographs of total binding or non-butaclamol-displaced ('non-specific') binding. The image processing system digitized each autoradiograph, attenuated geometric distortion and unevenness of background illumination, and reassigned the digitized image intensities (gray values) to be a linear function of fmol [3H]spiroperidol bound per mg protein by using a calibration curve generated from 3H-containing tissue standards. An image of butaclamol-displaced ('specific') [3H]spiroperidol binding was produced by subtracting the linearized image of non-specific binding from the superimposed image of total binding. An image of percent specific [3H]spiroperidol binding was obtained by dividing the image of specific binding by the superimposed image of total binding. The computer-derived images, which could be displayed in gray tones or pseudocolor-coded, revealed that the greatest amounts of specific [3H]spiroperidol binding (1000-3000 fmol/mg protein; 60-80% specifically bound) were located in layers 5A and 5C of the neocortex, the claustrum, and in the caudate-putamen, where a lateral-to-medial binding gradient occurred. [3H]Spiroperidol was bound to a lesser extent (400-1000 fmol/mg protein; 31-51% specifically bound) to the medial nucleus accumbens septi or olfactory tubercle and without measurable specificity to the lateral septum, anterior commissure, corpus callosum, or superficial neocortex. These procedures are particularly useful for the quantitative and visual analysis of autoradiographs in which [3H]ligand binding is associated with more than a single site.

Animals↗
PubMed1989

The effect of prototypic sigma ligands on the binding of [3H]dextromethorphan to guinea pig brain.

We studied the effects of several prototypic sigma site ligands on the binding of [3H]dextromethorphan ([3H]DM) to guinea pig brain. Haloperidol, 3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine [+)-3-PPP) and (+)-N-allyl-N-normetazocine [+)-NANM or (+)-SKF10,047), which are potent sigma site ligands, showed high affinity for [3H]DM binding sites. The rank order of potency of sigma ligands, as indicated by the Ki values for the high-affinity sites is: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than (+)-SKF10,047 greater than (-)-butaclamol much greater than (+)-butaclamol greater than (-)-SKF10,047. This rank order of potency is similar to that for the sites labeled with [3H](+)-3-PPP and [3H](+)-SKF10,047. The (+)-isomers of several benzomorphans displayed higher affinity than the (-)-isomers. (-)-Butaclamol competed against [3H]DM binding more effectively than the (+)-isomer, displaying the same stereospecificity shown for sigma sites. The findings reported here demonstrate that there are previously unrecognized similarities between DM and sigma sites. It is evident that further exploration of the DM, sigma and phencyclidine (PCP) sites will be necessary to establish the physiological role and therapeutic potential of these sites.

Animals↗
PubMed1986

Possible involvement of a hypothalamic dopaminergic receptor in development of genetic obesity in mice.

We have studied the binding of the dopaminergic agonist 2-[5,8-3H]amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene [( 3H]ADTN) to hypothalamic membranes from the genetically diabetic-obese (db/db) mice and their lean littermates. The specific binding of [3H]ADTN was defined as the difference between the radioligand binding to the membranes in the absence or presence of 1 microM (+)-butaclamol. In order to control nonspecific binding, all binding assays were performed in the presence of 0.1 mM catechol and 0.3 mM ascorbic acid. Binding of [3H]ADTN was rapid, dissociable, saturable and stereoselective. (+)-Butaclamol was very potent whereas (-)-butaclamol was ineffective in inhibiting the binding of this radioligand. Concentration-dependent binding experiments and Scatchard analysis of the data yielded dissociation constant (Kd) of 3.5-4.2 nM and number of binding sites (n) equivalent to 170-200 fmol/mg protein for lean mice. For db/db mice, the data yielded a Kd of 4.0-4.7 nM and an n of 400-500 fmol/mg protein. It was also shown that the anorexic drugs, amphetamine and fenfluramine, inhibited [3H]ADTN binding in a dose-dependent manner. Binding parameters, obtained using membranes from mice made obese by parenteral administration of gold thioglucose, were not significantly different from those obtained for the lean mice. It is concluded that the regulation of the hypothalamic dopaminergic receptors may be related to the lesion in the genetically obese mice.

Adenylyl Cyclases↗
PubMed1983

Pre- and postsynaptic effects of dopamine antagonists on dopaminergic synaptic transmission in Helix pomatia.

The rate of transmitter mobilization in identified dopaminergic synapses was decreased by the dopamine antagonists pimozide, chlorpromazine, haloperidol, cis-flupenthixol, curare, clozapine and high concentrations of ergometrine. The depolarizing postsynaptic potential was inhibited by pimozide, chlorpromazine, haloperidol, cis-flupenthixol, curare, clozapine, (+)-butaclamol and high concentrations of ergometrine. The hyperpolarizing synaptic potential was inhibited by naloxone, methysergide, (+)-butaclamol, haloperidol, 6-hydroxydopamine and low concentrations of ergometrine, while pimozide, cis-flupenthixol, trans-flupenthixol, curare, clozapine, promethazine, chlorpromazine and (-)-butaclamol had no clear effect. The presynaptic receptors involved in modulation of the mobilization rate showed similarities with the dopamine receptors mediating depolarizations. The dopamine antagonists changed dynamics of synaptic transmission.

Animals↗
PubMed1988

Affinity chromatography of the D1 dopamine receptor from rat corpus striatum.

The D1 dopamine receptor from rat corpus striatum has been purified 200-250-fold by using a newly developed biospecific affinity chromatography matrix based on a derivative of the D1 selective antagonist SCH 23390. This compound, (RS)-5-(4-aminophenyl)-8-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benz azepin-7-o l (SCH 39111), possesses high affinity for the D1 receptor and, when immobilized on Sepharose 6B through an extended spacer arm, was able to adsorb digitonin-solubilized D1 receptors. The interaction between the solubilized receptor and the affinity matrix was biospecific. Adsorption of receptor activity could be blocked in a stereoselective fashion [SCH 23390 greater than SCH 23388; (+)-butaclamol greater than (-)-butaclamol]. The elution of [3H]SCH 23390 activity from the gel demonstrated similar stereoselectivity for antagonist ligands. Agonists eluted receptor activity with a rank order of potency consistent with that of a D1 receptor [apomorphine greater than dopamine greater than (-)-epinephrine much greater than LY 171555 greater than serotonin]. SCH 39111-Sepharose absorbed 75-85% of the soluble receptor activity, and after the gel was washed extensively, 35-55% of the absorbed receptor activity could be eluted with 100 microM (+)-butaclamol with specific activities ranging from 250 to 450 pmol/mg of protein. The affinity-purified receptor retains the ligand binding characteristics of a D1 dopamine receptor. This affinity chromatography procedure should prove valuable in the isolation and molecular characterization of the D1 dopamine receptor.

Animals↗
PubMed2005

Mechanisms of inverse agonist action at D2 dopamine receptors.

Mechanisms of inverse agonist action at the D2(short) dopamine receptor have been examined. Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [3H]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. Competition of inverse agonists versus [3H]NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K(i) values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K(coupled) and K(uncoupled) were statistically different for the set of compounds tested (ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. These observations were supported by simulations of these competition experiments according to the extended ternary complex model. Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [35S]GTP gamma S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism.

Animals↗
PubMed1998

D2 dopamine receptors stimulate mitogenesis through pertussis toxin-sensitive G proteins and Ras-involved ERK and SAP/JNK pathways in rat C6-D2L glioma cells.

Dopamine D2 receptors are members of the G protein-coupled receptor superfamily and are expressed on both neurons and astrocytes. Using rat C6 glioma cells stably expressing the rat D2L receptor, we show here that dopamine (DA) can activate both the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) pathways through a mechanism involving D2 receptor-G protein complexes and the Ras GTP-binding protein. Agonist binding to D2 receptors rapidly activated both kinases within 5 min, reached a maximum between 10 and 15 min, and then gradually decreased by 60 min. Maximal activation of both kinases occurred with 100 nM DA, which produced a ninefold enhancement of ERK activity and a threefold enhancement of JNK activity. DA-induced kinase activation was prevented by either (+)-butaclamol, a selective D2 receptor antagonist, or pertussis toxin, an uncoupler of G proteins from receptors, but not by (-)-butaclamol, the inactive isomer of (+)-butaclamol. Cotransfection of RasN17, a dominant negative Ras mutant, prevented DA-induced activation of both ERK and JNK. PD098059, a specific MEK1 inhibitor, also blocked ERK activation by DA. Transfection of SEK1 (K --> R) vector, a dominant negative SEK1 mutant, specifically prevented DA-induced JNK activation and subsequent c-Jun phosphorylation without effect on ERK activation. Furthermore, stimulation of D2 receptors promoted [3H]thymidine incorporation with a pattern similar to that for kinase activation. DA mitogenesis was tightly linked to Ras-dependent mitogen-activated protein kinase (MAPK) and JNK pathways. Transfection with RasN17 and application of PD098059 blocked DA-induced DNA synthesis. Transfection with Flag delta169, a dominant negative c-Jun mutant, also prevented stimulation of [3H]thymidine incorporation by DA. The demonstration of D2 receptor-stimulated MAPK pathways may help to understand dopaminergic physiological functions in the CNS.

Animals↗
PubMedDate not supplied

Characterization of vascular dopamine receptors in the gastric circulation of the rabbit.

An in vivo model is presented for studying the vasodilator effect of dopamine on the gastric vascular bed of the anesthetized rabbit. Dopamine was injected into the common hepatic artery simultaneously measuring the blood flow through the left gastric artery at constant perfusion pressure. The vasoconstrictor response to dopamine was blocked by pretreatment with phenoxybenzamine (0.5 mg/kg i.a.). Dopamine dilated the gastric vascular bed dose-dependently with an average ED50 of 15 nmol. Apomorphine caused vasodilation with an ED50 of 38.8 nmol; the maximum response was significantly lower than dopamine. (-)Isoproterenol was ineffective. cis-Flupentixol (3.5 and 7.0 mumol/kg i.v.) and (+)butaclamol (3.0 mumol/kg i.v.), but not trans-flupentixol (7.0 mumol/kg i.v.) and (-)butaclamol (6.0 mumol/kg i.v.) shifted the dopamine dose-response curve to the right in a parallel fashion, indicating competitive antagonism. Haloperidol, bulbocapnine, and sulpiride also acted as competitive inhibitors of dopamine-induced vasodilation. The antagonists inhibited the dopamine-induced vasodilation in the following order of potency: (+)butaclamol greater than cis-flupentixol greater than haloperidol greater than bulbocapnine greater than sulpiride. The results suggest that the vascular dopamine receptors in the stomach of the rabbit resemble the DA1-receptors in the mesenteric vascular bed of dogs.

Animals↗
PubMed1982

[3H]Apomorphine binding to a GTP-sensitive dopaminergic site in bovine anterior pituitary gland.

The characteristics of binding of the potent dopaminergic agonist [3H]apomorphine have been studied in bovine anterior pituitary membranes. A high affinity binding site with an apparent dissociation constant (KD) of 0.7 nM and a number of binding sites of 56 fmol/mg protein has been measured when 10(-5) M dopamine was used to assess nonspecific binding. The order of potency of various agonists to compete with [3H]apomorphine binding is consistent with an interaction at a typical dopaminergic receptor: apomorphine greater than dopamine greater than (-)-epinephrine = (-)-norepinephrine much greater than (-)-isoproterenol. Competition for [3H]apomorphine binding by antagonists shows marked stereoselectivity, (+)-butaclamol being 4000 times more potent than (-)-butaclamol. Dihydroergocryptine, a potent dopaminergic agonist on prolactin release, as well as the dopaminergic antagonists spiroperidol, haloperidol, and (+)-butaclamol, compete for [3H]apomorphine binding at nanomolar concentrations. By contrast, adrenergic (phentolamine, propranolol, and clonidine) and serotonergic (serotonin, cyproheptadine, and methysergide) agonists and antagonists do not compete or are weak competitors at micromolar concentrations. Guanosine triphosphate (GTP) decreases [3H]apomorphine binding, the affinity of this ligand for the receptor being decreased 10 times by 300 microM GTP. The close correlation observed between the affinity of a series of agonists and antagonists for the [3H]apomorphine binding sites and their potency as modulators of prolactin release suggests that [3H]apomorphine binding sites are those involved in the control of prolactin secretion.

Animals↗
PubMed1983

Dopamine receptors on intact anterior pituitary cells in culture: functional association with the inhibition of prolactin and thyrotropin.

Dopamine (DA) and the dopaminergic agonists bromocriptine and apomorphine inhibit the secretion of TSH as well as that of PRL by rat anterior pituitary (AP) cells in monolayer culture. The order of potency of the drugs is the same for the inhibition of both hormones: bromocriptine ED50 = 0.006 nM against PRL and 0.017 nM against TSH; apomorphine ED50 = 2.9 and 4.8 nM, respectively, and DA, ED50 = 30 and 370 nM, respectively. The dopaminergic antagonists domperidone (DOM) and metoclopramide prevent the inhibition of TSH and PRL by 10(-6) M DA (IC50 = 0.012 and 0.32 nM for metoclopramide against PRL and TSH, respectively; similarly, IC50 = 0.01 and 0.61 nM for DOM). The action of butaclamol is shown to be stereospecific, in that the (+) isomer is 1000-fold more potent in reversing the inhibition of both TSH and PRL by 10(-6) M DA than the (-) isomer [IC50 = 1.1 and 7200 nM for the (+) and (-) isomers against PRL; similarly, 6.3 and 2600 nM against TSH]. The use of radioligand-binding techniques with tritiated DOM ([3H]DOM) and dihydroergocriptine ([3H]DHE) has demonstrated a high affinity dopaminergic binding site upon rat AP cells under the same conditions as the cell cultures used in the hormone secretion studies. Both ligands have been shown to label a site with high affinity (Kd = 1-2 nM) and low capacity (2-3 fmol/10(5) cells). At this site, dopaminergic agonists and antagonists compete with both radioligands and display a rank order of potency which is the same as that shown against TSH and PRL secretion and which is typically dopaminergic. For [3H]DHE: bromocriptine Ki (0.04 nM) greater than metoclopramide = DOM (0.07 nM) greater than (+)butaclamol (0.7 nM) greater than apomorphine (20 nM) greater than DA (700 nM) greater than (-)butaclamol (2000 nM). Similar data were derived using [3H]DOM. The high affinity site is saturable, has rapid association and dissociation rates, as determined for both radioligands used, and is temperature dependent. In contrast, both radioligands bind to a second binding site on the cells that is of lower affinity (Kd = 244 nM for [3H]DOM and 678 nM for [3H]DHE) and larger capacity (100 fmol/10(5) cells for both ligands). This second site is neither stereospecific nor, using the methodology presented here, does it discriminate between other dopaminergic compounds. It is thus not considered to represent specific DA receptor binding. It is concluded that the dopaminergic stimulus causing the inhibition of TSH and PRL secretion from rat AP cells in culture is mediated via a high affinity DA receptor present upon lactotrophs and thyrotrophs and that this receptor has similar characteristics on the two cell types.

Animals↗
PubMed1984

Hypothyroid pituitary cells in culture: an analysis of thyrotropin and prolactin responses to dopamine (DA) and DA receptor binding.

Monolayer cultures were prepared from the anterior pituitary (AP) lobes of normal male rats and male rats made hypothyroid by treatment with aminotriazole. After 3 days in culture, the cells from hypothyroid animals showed significantly greater TSH and PRL secretory activity and significantly less GH secretory activity than did parallel euthyroid cultures. The responses of euthyroid and hypothyroid cultures to dopaminergic agonists and antagonists were examined. Bromocriptine, apomorphine, and dopamine (DA) inhibited euthyroid TSH secretion by approximately 30%, whereas each drug inhibited hypothyroid TSH secretion by approximately 60% (P less than 0.01 for each drug). In contrast, the three agonists were less effective in inhibiting PRL secretion from hypothyroid cells (P less than 0.05 for each drug). The rank order of potency [bromocriptine greater than (+)butaclamol greater than apomorphine greater than DA greater than (-)butaclamol] shown against secretion was the same for TSH and PRL in both euthyroid and hypothyroid cell cultures and is typical of a DA receptor-mediated process. The binding of [3H]dihydroergocryptine (DHE) to DA receptors on euthyroid and hypothyroid cells was examined under the same conditions in which the secretory responses were determined. One micromolar concentration of (+)butaclamol was used to define nonspecific binding. Specific binding was saturable and stereospecific in each case. The rank order of potency of dopaminergic agonists and antagonists in competing for [3H] DHE binding was the same as that demonstrated against the secretion of TSH and PRL. Each compound displaced significantly more [3H]DHE from hypothyroid cells than from euthyroid cells (P less than 0.05 for each drug). Construction of adsorption isotherms for [3H]DHE binding to DA receptors on euthyroid and hypothyroid cells and subsequent Scatchard analysis revealed a 3- to 4-fold increase in receptor number without a significant change in affinity. Immunohistochemistry on AP lobes before and after dispersion revealed an increase in thyrotrophs and thyroidectomy cells in hypothyroid rats relative to those in control animals. In euthyroid animals thyrotrophs were 10.1% of the total AP cell population, in hypothyroid animals they plus the thyroidectomy cells were 36.3% of the total AP cells. Therefore, the increased number of DA receptors per lobe could be accounted for by increased numbers of thyrotrophs. The mechanism of the altered sensitivity to DA induced by hypothyroidism in lactotrophs and thyrotrophs remains to be clarified.

Animals↗
PubMed1992

Presence of dopamine D1 receptors and absence of dopamine D2 receptors in human cerebral meningioma tissue.

Preliminary studies have shown that the dopamine D1 receptor is expressed in cerebral meningioma tissue. The current study presents evidence that the iodinated dopamine D1 antagonist [125I]SCH-23982 bound to dopamine binding sites in 33 of the 45 human cerebral meningiomas examined for this. Saturation curves and the linearity of the Scatchard analysis indicate that [125]SCH-23982 binds to a homogeneous population of binding sites. Competition curves reveal the presence of a dopamine D1 receptor by rank order of various dopaminergic and nondopaminergic antagonists ((+)-SCH-23390 greater than (+/-)-SKF-83566 greater than (cis)-flupentixol greater than (+)-butaclamol greater than chlorpromazine greater than 1-sulpiride greater than mianserin greater than (-)-butaclamol). Stereoselectivity was evaluated by (+)- and (-)-butaclamol. The mean (+/- standard deviation) dissociation rate constant was 369 +/- 196 pM with a density of 31.9 +/- 12.5 fmol/mg membrane protein among 33 meningiomas. The dopamine D2 receptor was not present in the 30 meningiomas examined for this. These findings indicate that the dopamine D1 receptor identified is expressed alone and is therefore regulated independent of a D2 receptor in cerebral meningioma tissue. Although the function of the dopamine D1 receptor in cerebral meningiomas has not so far been defined, previous studies have suggested that the D1 receptor might be involved in the control of proliferative growth of meningiomatous tissue.

Adult↗
PubMed1985

Computer imaging and analysis of dopamine (D2) and serotonin (S2) binding sites in rat basal ganglia or neocortex labeled by [3H]spiroperidol.

The equilibrium properties, pharmacological specificity and regional distribution of serotonin (S2) and dopamine (D2) binding sites in coronal or horizontal rat brain sections labeled by [3H] spiroperidol were investigated by computer analysis of digitized autoradiographs. Domperidone or (+)-butaclamol displaced [3H] spiroperidol from the anterior caudate-putamen, nucleus accumbens, olfactory tubercle, claustrum, layer 5A of motor cortex and layer 1 of the anterior cingulate cortex (IC50 = 2-80 nM). Equilibrium saturation analysis of the (+)-butaclamol-displaced binding of [3H]spiroperidol revealed higher binding affinities in the anterior caudate-putamen, nucleus accumbens and olfactory tubercle (Kd = 0.16-0.32 nM) than in the claustrum or layer 5A of motor cortex (Kd = 1.5-1.9 nM). The [3H]spiroperidol binding displaced by (+)-butaclamol was resolved into a dopaminergic (D2) component, displaced by 100 microM 2-amino-6,7-dihydroxytetrahydronapthalene or 10 microM (-)-sulpiride and a serotonergic (S2) component, displaced by 40 nM ketanserin or 100 nM methysergide. Methysergide or ketanserin displaced [3H]spiroperidol only from the caudal (peripallidal) caudate-putamen, claustrum or layer 5A of motor cortex (IC50 = 2-14 nM), whereas the D2 agonist 2-amino-6,7-dihydroxytetrahydronapthalene displaced [3H]spiroperidol from the caudate-putamen but not from cortex. The competition curve for 2-amino-6,7-dihydroxytetrahydronapthalene displacement of [3H]spiroperidol binding to D2 sites in the caudate-putamen was markedly biphasic and shifted to the right by the GTP analog, guanylimidodiphosphate. The D2 antagonist (+/-)- or (-)-sulpiride also displaced [3H]spiroperidol from the nucleus accumbens and olfactory tubercle as well as from the caudate-putamen (IC50 values = 0.14 microM). In contrast, the butyrophenone derivative, spirodecanone, displaced with equal potency all [3H]spiroperidol from each of the six brain regions. Neither the alpha-1 receptor ligand prazosin nor the excitatory amino acid receptor ligands l-aspartate, l-glutamate or dl-homocysteic acid displaced [3H]spiroperidol from any brain area. A 5-fold rostral-to-caudal gradient of decreasing S2 concentration was observed in neocortical layer 1 of horizontal sections. In the caudate-putamen, D2 density decreased by 30% rostrocaudally, whereas S2 sites were located mostly in the peripallidal caudate-putamen. The rostral-to-caudal gradients of D2 or S2 sites in the caudate-putamen correspond remarkably well with previously reported caudate-putamen concentration gradients for dopamine or serotonin, respectively.

Animals↗
PubMed1983

Synthesis and pharmacological study of the thiophene analogue of taclamine, QM-7184, a new neuroleptic drug with potent alpha-adrenoceptor blocking activity.

The method of synthesis and the pharmacological evaluation of (+/-)-6-trans-8b,9,10,11,12,13-trans-13a-Octahydro-5H-7-thia-12a-azabenzo[f]naphth[1,2,3-c,d] azulene (QM-7184), a thiophene analogue of taclamine, are reported. This new drug shows, at variance with the prototype, a neuroleptic profile in rodents. QM-7184 decreases the spontaneous motor activity, blocks the stereotyped behaviour induced by dopaminergic stimulants and reduces conditioned avoidance responses. In all of these tests, the new drug is less potent than the typical neuroleptics haloperidol or butaclamol. Taclamine does not show, as expected, any neuroleptic activity. Like other neuroleptics, QM-7184 blocks striatal dopaminergic receptors and consequently increases the concentration of homovanillic acid and displaces [3H]spiperone binding, although it is a less potent displacer than haloperidol or butaclamol. QM-7184 shows, however, a high affinity for alpha-noradrenergic receptors, both in the cortex and in the striatum, which is about 20 and 90 times higher than those of haloperidol and butaclamol, respectively. In view of the recently suggested role for norepinephrine in the etiology of schizophrenia, it is speculated that drugs of this type may be of interest in the treatment of psychotic illness.

Adrenergic alpha-Antagonists↗
PubMed1980

Binding of [3H]pergolide mesylate to dopamine receptors of mammalian brains.

The ergoline dopamine agonist, [3H]pergolide, binds with pharmacological specificity to particulate fractions of rat and calf brains. Dopamine agonists (apomorphine, 5,6-dihydroxy-2-dimethylaminotetralin, 6.7-dihydroxy-2-methylaminotetralin, lergotrileand bromocriptine) and dopamine antagonists (haloperidol and (+)butaclamol but not its pharmacologically inactive isomer, (-)butaclamol) were potent inhibitors, while monoamines (dopamine, norepinephrine, epinephrine and serotonin) were weaker inhibitors of [3H]pergolide binding. Olfactory tubercle was the only brain region other than striatum which exhibited significant [3H]pergolide binding displaceable by 1 microM (+)butaclamol. Saturable of calf and rat striatum with dissociation constants, kd values, of 1.2 to 3.1 nM. The number of binding sites was enriched in crude synaptosomal fractions. The relationship of [3H]pergolide binding to the binding of other dopaminergic ligands is discussed.

Animals↗
PubMed1982

Neuroleptic-induced seizures. An in vitro technique for assessing relative risk.

To estimate the relative risk of various neuroleptic medications for patients with epilepsy or likely to have neuroleptic-induced seizures, their action on spike activity in perfused guinea pig hippocampal slices was studied. Within the range of concentrations studied, molindone hydrochloride, butaclamol hydrochloride, pimozide, and fluphenazine dihydrochloride produced the least increase in excitability. There were also differences in the dose-response curves. Chlorpromazine, thioridazine, and pimozide produced an inverted U-shaped curve. For haloperidol and fluphenazine, excitability tended to increase and them plateau. Molindone and butaclamol produced no increase in excitability. Combinations of neuroleptics had synergistic effects, while the anticonvulsant diazepam inhibited neuroleptic-induced excitability. This article discusses the clinical implications of these findings and their effect on theories of which neuroleptics might produce the fewest seizures.

Animals↗
PubMed1992

Specific [3H]raclopride binding to neostriatal dopamine D2 receptors: role of disulfide and sulfhydryl groups.

Receptor binding studies were performed in rabbit neostriatum (caudate-putamen) using the dopamine D2 antagonist [3H]raclopride. Treatment of the membrane preparations with the reducing agent L-dithiothreitol (L-DTT) as well as with the alkylating compound N-ethylmaleimide (NEM), produced dose-dependent decreases of specific [3H]raclopride binding; the IC50 values were of 3.1 and 1.2 mM, respectively. Saturation experiments showed that the reduction of disulfide (-S-S-) bonds by L-DTT (1 mM) decreased the number of binding sites, with only a slight increase in the affinity. On the other hand, alkylation of sulfhydryl (-SH) groups by NEM (1 mM) decreased both receptor number and affinity. The properties of the remaining binding sites were examined in competition curves with the physiological substrate dopamine and the dopaminergic antagonist (+)butaclamol. The IC50 values for (+)butaclamol in control and in L-DTT and NEM treated membranes were between 3.4 and 4.8 nM, with Hill coefficients (nH) of 1, indicating that the remaining binding sites conserved a high affinity for antagonist binding. In the case of dopamine, the curves were shallow (nH 0.45-0.64) and both compounds increased the IC50 from 0.7 microM (control) to 8 microM and 11 microM, for L-DTT and NEM respectively. Iterative analysis revealed that L-DTT produced a very important (greater than 60%) decrease in the number of high-affinity (RH) binding. After NEM, there was a decrease in both the number of (RH) and the affinity (KH) of the high-affinity binding sites, and in the affinity (KL) of the low-affinity sites. These results demonstrate the participation of -S-S- and -SH groups in the agonist conformation of the primary ligand recognition site of the dopamine D2 receptor. Alternatively, -S-S- and -SH groups could be related to the coupling of the primary ligand recognition protein with adenylate cyclase by means of an inhibitory type of G protein.

Alkylation↗
PubMed1993

Myocardial accumulation of a dopamine D2 receptor-binding radioligand, 2'-iodospiperone.

125I-2'-iodospiperone (2'-ISP), which has a high and selective affinity for dopamine D2 receptors, produced a high myocardial accumulation of radioactivity in the early phase after intravenous injection into mice. A human scintigraphic study also showed that the myocardium was clearly visualized soon after intravenous injection of the tracer. Analysis of the myocardial homogenate obtained from mice showed that 125I-2'-ISP was metabolically stable and was taken up the myocardium in its intact form. Administration of spiperone significantly reduced the myocardial uptake of 125I-2'-ISP in mice. Treatment with haloperidol and (+) butaclamol, which have a high affinity for dopamine D2 receptors, also tended to reduce the myocardial uptake of radioactivity, while (-)-butaclamol, which has no affinity for dopamine D2 receptors, caused no change in uptake. These findings suggest that the myocardial accumulation of 2'-ISP occurred in association with dopamine D2 (DA2) receptors.

Animals↗