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PubMed1989

Opioid- and phencyclidine-like discriminative effects of ditolylguanidine, a selective sigma ligand.

The sigma binding site in brain has affinity for psychotomimetic opioids, phencyclidine (PCP) and antipsychotic drugs, and is a separate entity from the PCP receptor. In order to demonstrate a behavioral correlate of sigma binding, rats were trained to discriminate between s.c. injections of saline and 3.0 mg/kg of ditolylguanidine (DTG), a selective and high affinity sigma ligand, and tested for generalization to novel drugs. The rats generalized dose dependently and completely or almost completely to PCP and related drugs and to mu, kappa and sigma opioid agonists. A separate group of rats trained to discriminate saline from 2.0 mg/kg of PCP generalized completely to DTG, confirming the commonalities in the discriminative effects of these drugs. DTG-like discriminative effects of opioid enantiomers showed no consistent stereoselectivity. Discriminative effects of the DTG training dose were neither mimicked by haloperidol and (-)-butaclamol, which have high affinity for the sigma site, or by the opioid antagonist naltrexone. Order of potency in producing DTG-like discriminative effects did not correlate with published reports of relative drug affinity for the sigma site or the PCP receptor. Although the discriminative effects of DTG have commonalities with those of several types of opioid and PCP-like drugs, their pharmacologic characteristics are different from the pharmacologic characteristics of opioid and PCP receptors as well as from those of the sigma binding site.

Animals↗
PubMed1989

Functional characterization of a rat dopamine D-2 receptor cDNA expressed in a mammalian cell line.

We recently cloned a complementary DNA for the rat dopamine D-2 receptor, making it possible to create cell lines expressing this receptor. A cell line (LZR1) was created by transfecting the D-2 cDNA (RGB-2) into mouse fibroblast Ltk- cells. LZR1 cells, previously described as L-RGB2Zem-1 cells, express a high density of D-2 receptors, whereas the wild-type cells do not. A number of agonists competitively and stereoselectively inhibited the binding of [3H]spiroperidol to the expressed D-2 receptors in a GTP-sensitive manner. The potency of dopamine was decreased by the addition of GTP. NaCl and GTP together caused a further decrease in potency and increased the Hill slope for inhibition of radioligand binding by dopamine almost to 1.0. Pretreatment of cells with pertussis toxin inhibited high affinity binding of dopamine and prevented further inhibition of binding by GTP. The NaCl-induced decrease in affinity was not prevented by pertussis toxin treatment. Dopamine reduced forskolin-stimulated adenylate cyclase activity by 27% in membranes prepared from LZR1 cells. Inhibition by dopamine was blocked by (+)-butaclamol or prior treatment of intact cells with pertussis toxin. Other dopamine receptor agonists stereoselectively inhibited adenylate cyclase activity. These data indicate that the RGB-2 cDNA directs the expression of a dopamine D-2 receptor capable of interacting with guanine nucleotide-binding proteins and inhibiting adenylate cyclase activity. Furthermore, the RGB-2 cDNA provides a means of creating many cell lines that will be useful tools for the biochemical and pharmacological characterization of dopamine D-2 receptors.

Adenylate Cyclase Toxin↗
PubMed1987

[The beta-adrenergic receptor and adenylate cyclase of rat reticulocytes as a test system for screening pharmacologic preparations].

The effect of cardio- and neurotropic drugs was studied on beta 2-adrenergic receptors and coupled adenylate cyclase (AC) from rat reticulocytes. Trifluperazine, chlorpromazine, levomepromazine, metaphenazine, haloperidol, (+) and (-) isomers of butaclamol, as well as imipramine, vinblastine and verapamil, at a concentration of 10(-4) M failed to influence AC stimulation by isoproterenol. Thioproperazine and trifluperidol inhibited isoproterenol-stimulated AC with Ki = 4.0.10(-5) M and Ki = 4.5.10(-5) M, respectively. This inhibitory effect was due to the direct action of thioproperazine and trifluperidol on the beta-adrenergic receptors, since this drugs displace the receptor-bound (3H) dihydroalprenolol with Ki = 5.10(-6) M and 9.10(-6) M, respectively. The results obtained suggest that adrenolytic effect of trifluperidol and thioproperazine might play a significant role in their side effects.

Adenylyl Cyclases↗
PubMed1987

Characterization of D-2 dopamine receptors in a tumor of the rat anterior pituitary gland.

Dopamine receptors in the 7315a transplantable rat anterior pituitary tumor were characterized using radioligand binding assays with [3H]spiroperidol ([3H]SPD) and assays of adenylate cyclase activity. Scatchard analysis of the binding of [3H]SPD yielded linear plots and a Kd value of 73 pM. Studies of the inhibition of the binding of [3H]SPD were performed with a series of competing ligands, including the antagonists domperidone, (+)-butaclamol and sulpiride and the agonists dopamine, bromocriptine and N-propylnorapomorphine. Inhibition curves for the antagonists gave Hill coefficients of approximately 1, consistent with the presence of only a single class of binding sites with a high affinity for [3H]SPD. In contrast, the Hill coefficient for dopamine was significantly less than 1. When assays were carried out in the presence of 300 microM GTP, the inhibition curve for dopamine was shifted to the right and the Hill coefficient increased to approximately 1. An effect of GTP on the affinity of a receptor for agonists is consistent with the existence of at least two agonist affinity states. Inhibition of the binding of [3H]SPD by the partial agonist bromocriptine was not affected when assays were carried out in the presence of GTP. The uniform low affinity of the selective serotonin antagonist ketanserin for these sites indicated that the radioligand was not labeling serotonin-2 receptors in this tissue. A good correlation was observed between the Ki values for competing ligands measured in the tumor and in homogenates of rat striatal tissue. Dopamine was shown to inhibit forskolin-stimulated adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1987

Pharmacological and biochemical characterization of the D-1 dopamine receptor mediating acetylcholine release in rabbit retina.

Superfusion with dopamine (0.1 microM-10 mM) evokes calcium-dependent [3H]acetylcholine release from rabbit retina labeled in vitro with [3H]choline. This effect is antagonized by the D-1 dopamine receptor antagonist SCH 23390. Activation or blockade of D-2 dopamine, alpha-2 or beta receptors did not stimulate or attenuate the release of [3H]acetylcholine from rabbit retina. Dopamine receptor agonists evoke the release of [3H]acetylcholine with the following order of potency: apomorphine greater than or equal to SKF(R)82526 greater than SKF 85174 greater than SKF(R)38393 greater than or equal to pergolide greater than or equal to dopamine (EC50 = 4.5 microM) greater than SKF(S)82526 greater than or equal to SKF(S)38393. Dopamine receptor antagonists inhibited the dopamine-evoked release of [3H]acetylcholine: SCH 23390 (IC50 = 1 nM) greater than (+)-butaclamol greater than or equal to cis-flupenthixol greater than fluphenazine greater than perphenazine greater than trans-flupenthixol greater than R-sulpiride. The potencies of dopamine receptor agonists and antagonists at the dopamine receptor mediating [3H]acetylcholine release is characteristic of the D-1 dopamine receptor. These potencies were correlated with the potencies of dopamine receptor agonists and antagonists at the D-1 dopamine receptor in rabbit retina as labeled by [3H]SCH 23390, or as determined by adenylate cyclase activity. [3H]SCH 23390 binding in rabbit retinal membranes was stable, saturable and reversible. Scatchard analysis of [3H]SCH 23390 saturation data revealed a single high affinity binding site (Kd = 0.175 +/- 0.002 nM) with a maximum binding of 482 +/- 12 fmol/mg of protein. The potencies of dopamine receptor agonists to stimulate [3H]acetylcholine release were correlated with their potencies to stimulate adenylate cyclase (r = 0.784, P less than .05, n = 7) and with their affinities at [3H]SCH 23390 binding sites (r = 0.755, P greater than .05, n = 8). The potencies of antagonists to inhibit dopamine-evoked [3H]acetylcholine release were correlated with their potencies to inhibit the dopamine-stimulated adenylate cyclase (r = 0.759, P less than .05, n = 5) and with their affinities at [3H]SCH 23390 binding sites (r = 0.998, P less than .01, n = 7). We conclude that in rabbit retina dopamine evokes calcium-dependent [3H]acetylcholine release through activation of a site with the pharmacological characteristics of a D-1 dopamine receptor.

Acetylcholine↗
PubMed1988

Binding of [125I]-N-(p-aminophenethyl)spiroperidol to the D-2 dopamine receptor in the neurointermediate lobe of the rat pituitary gland: a thermodynamic study.

The novel iodinated ligand [125I]-N-(p-aminophenethyl)spiroperidol ([125I]NAPS) was used to identify the D-2 dopamine receptor in the intermediate lobe of the rat pituitary gland. The binding of [125I]NAPS was of high affinity and saturable, given that the dissociation constant and the maximal binding were 34.7 +/- 4.8 pM and 21.1 +/- 2.5 fmol/mg of protein, respectively. The ability of dopaminergic agonists and antagonists to compete with [125I]NAPS varied markedly with incubation temperature. The marked decrease of the molar potency associated with increasing incubation temperature in the competitive displacement curve suggested that the binding of five agonists, dopamine, (-)-apomorphine, (-)-n-propylnorapomorphine, N-0434, and LY-171555, to the D-2 dopamine receptor was enthalpy-driven, with a negative change in entropy. In contrast, the binding of three antagonists, fluphenazine, (+)-butaclamol, and domperidone, was entropy-driven, with positive change in entropy, suggesting less temperature-sensitive change in the molar potency. Several molecules gave unanticipated results; the molar potency of two dopamine agonists, bromocriptine and lisuride, was much less temperature-sensitive than the other agonists used in this study. The thermodynamic parameters for the atypical agonists indicated entropy-driven binding. Conversely, the molar potency of (+)-apomorphine, a dopamine receptor antagonist, was markedly affected by incubation temperature, indicating enthalpy-driven binding. Another antagonist, YM-09151-2, was affected by the inclusion of sodium chloride in the assay system: in the absence of sodium chloride, the drug was relatively weak and displayed enthalpy-driven binding; in the presence of sodium chloride, its molar potency was increased and its binding manner turned into entropy-driven.

Animals↗
PubMed1988

[3H]SCH 23390 labels both dopamine-1 and 5-hydroxytryptamine1c receptors in the choroid plexus.

[3H]SCH 23390 has been used to label the D-1 subtype of dopamine receptors. Quantitative autoradiographic studies with [3H]SCH 23390 have revealed high levels of binding in many regions of rat brain including the caudate-putamen, nucleus accumbens, substantia nigra and choroid plexus. The selectivity of the binding of [3H]SCH 23390 was characterized further in studies using homogenates of canine choroid plexus. Scatchard analysis of the binding of increasing concentrations of [3H]SCH 23390 resulted in a curvilinear plot when (+)-butaclamol was used to define specific binding. Nonlinear regression analysis of untransformed data was consistent with the presence of two distinct classes of binding sites. The high-affinity site (Kd, 0.4 nM) was present at low density (maximum binding sites, 30 fmol/mg of protein) and had the pharmacological properties expected of a D-1 receptor. The low-affinity site (Kd, 24 nM) was present at a much greater density (maximum binding sites, 350 fmol/mg of protein) and had the pharmacological properties expected of a 5-hydroxytryptamine1c receptor. Quantitative autoradiographic studies of the binding of [3H]SCH 23390 to sections of rat brain also suggested that 5-hydroxytroptamine1c receptors in the choroid plexus are labeled by [3H]SCH 23390. It is possible that [3H]SCH 23390 labels 5-hydroxytryptamine1c receptors in other brain regions as well.

Animals↗
PubMed1986

[Comparison of the vasomotor effects of dopamine on the renal and iliac arterial beds of the anesthetized rat].

Dopamine remains the reference in the study of the mechanisms involved in the antihypertensive effects of dopaminomimetics. Its renal vasodilator effects are well characterized but relaxation of other vascular beds is less known. The iliac vascular response to dopamine was studied in the anesthetized rat (pentobarbital) and compared to the renal response. Simultaneous measurements of arterial pressure, iliac and renal blood flows (electromagnetic flowmeter probes, Skalar, Delft) allowed iliac and renal vascular resistance (IVR, RVR) to be calculated. Their variations were studied after intravenous injections of increasing doses of dopamine (1.5 to 200 micrograms/kg) in unpretreated animals and in animals receiving various pretreatments. Without pretreatment, dopamine induced a biphasic renal response, vasodilation partially masked by subsequent vasoconstriction for doses above 12.5 micrograms/kg of dopamine. Simultaneously, IVR was increased. After alpha-adrenolytic pretreatment (prazosin 2.5 mg/kg, i.v.), dopamine decreased the RVR while iliac vasoconstriction persisted. The association of yohimbine (5 mg/kg, i.v.) to prazosin completely abolished the vasoconstrictive effects: dopamine lowered then by about 30% both IVR and RVR. Dopamine-induced iliac and renal decrease in vascular resistance persisted in the presence of a beta-adrenoceptor antagonist [+/-)-sotalol 30 mg/kg, i.v.), after depletion of catecholamines from sympathetic terminals (reserpine 10 mg/kg, i.p. 20 h before the experiment) or inhibition of cyclo-oxygenase (indomethacin 2.5 mg/kg, i.p. 20 h and 1 h before dopamine). On the contrary, a specific antagonist of dopamine receptors, (+)-butaclamol (60 micrograms/kg/min, i.v.) stereoselectivity inhibited the dopamine-induced renal vasodilation but did not modify the iliac response.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗
PubMed1987

An islet activating protein-sensitive G protein is involved in dopamine inhibition of angiotensin and thyrotropin-releasing hormone-stimulated inositol phosphate production in anterior pituitary cells.

In primary culture of anterior pituitary cells, dopamine inhibited the angiotensin (AII)-stimulated inositol phosphate production by 28 +/- 2.5% (n = 14), with an EC50 of 660 +/- 228 nM (n = 8). This effect was blocked by (+)-butaclamol, a specific dopamine receptor antagonist. RU 24926, a D2 specific agonist, but not SKF 38393, a specific D1 agonist, inhibited AII-stimulated inositol phosphate production, suggesting that this dopamine effect is mediated through a dopamine receptor of the D2 subtype. Dopamine also partially inhibited (25%) inositol phosphate production stimulated by thyrotropin-releasing hormone (TRH). Our results suggest that the dopamine-mediated inhibition of hormonally stimulated inositol phosphate production is probably not mediated through the known inhibitory effects of dopamine on cAMP and Ca2+ intracellular concentrations. Although unknown, the mechanism by which dopamine inhibited the AII and TRH-stimulated inositol phosphate production implicates a GTP binding protein sensitive to the islet activating protein (IAP) since dopamine effects were blocked by this toxin. The alpha subunit of the GTP binding protein involved could be one of the three ADP-ribosylated proteins found in anterior pituitary cells in primary cultures, the alpha o (39 kDa), the alpha i (41 kDa), and an alpha subunit of 40 kDa. Indeed, we show here that this 40-kDa IAP substrate, already described in a few tissues, is present in anterior pituitary cells. The negative coupling between dopamine receptors and the AII or TRH inositol phosphate production systems, could be implicated in the dopamine inhibition of the AII- and TRH-stimulated prolactin release since such an inhibition is blocked by IAP. Our results suggest that the negative regulation of inositol phosphate production is one of the mechanisms by which dopamine controls hormonally stimulated prolactin release.

Adenosine Diphosphate Ribose↗
PubMed1988

Interaction of [3H]spiperone with rat striatal dopamine D-2 receptors: kinetic evidence for antagonist-induced formation of ternary complex.

The characteristics of [3H]spiperone interactions with rat striatal dopamine D-2 receptor were investigated. Although the association of [3H]spiperone occurred monoexponentially, the pseudo-first order rate constant of association showed a hyperbolic dependence on ligand concentration. The data were therefore analyzed with the assumption of a two-step binding reaction leading to ligand-induced receptor isomerization. For the first equilibrium, the dissociation constant (KD) was 1.2 nM, while for the second equilibrium, the association and the dissociation rate constants were 71.6 X 10(-3) sec-1 and 0.9 X 10(-3) sec-1, respectively. The dissociation rate constant of the overall binding reaction, as determined by inducing the dissociation of [3H]spiperone from its binding sites by 1 microM (+)-butaclamol, was 0.92 X 10(-3) sec-1. However, the kinetically derived KD (15 pM) of the binding reaction differed significantly from the KD (218 pM) obtained from equilibrium binding experiments. This inconsistency between the two KD values appeared to have arisen from using different receptor concentrations in deriving kinetic and equilibrium data. The KD of the equilibrium binding reaction indeed showed significant variation with the receptor concentrations in an inverse way, implicating the involvement of a third component in the two-step binding reaction to form a high affinity ternary complex rather than a simple ligand induced receptor isomerization. Pretreatment of the membrane with 0.1 mM guanosine 5'-imidodiphosphate [Gpp(NH)p] reduced the affinity of the equilibrium binding reaction to a value (KD = 1.2 nM) which corresponded to the kinetically derived KD of the first step of the binding reaction, indicating the involvement of a guanine nucleotide-binding protein or G protein in inducing the formation of the high affinity ternary complex. The affinity of the binding reaction in Gpp(NH)p-pretreated membranes, however, increased with the duration of incubation, indicating that the ligand receptor complex still can couple with the G protein even in the presence of Gpp(NH)p. Pretreatment of the membrane with pertussis toxin irreversibly decreased the affinity of the binding reaction without significantly affecting the total number of binding sites, implying the involvement of the Gi subclass of G protein in the interaction of [3H]spiperone with D-2 receptors. Inhibition of the [3H]spiperone binding by a dopamine receptor agonist, bromocriptine, also yielded a monophasic dose response curve both in the presence and in the absence of Gpp(NH)p.(ABSTRACT TRUNCATED AT 400 WORDS)

Algorithms↗
PubMed1987

No-carrier-added N-(3-[18F]fluoropropyl)spiroperidol: biodistribution in mice and tomographic studies in a baboon.

Two potential radioligands, no-carrier-added (NCA) N-(2-[18F]fluoroethyl)spiroperidol (3) and N-(3-[18F]fluoropropyl)spiroperidol (4) have been synthesized for PET imaging of dopamine receptors in humans. Compounds 3 and 4 were synthesized by N-alkylation of spiroperidol with NCA 1-bromo-2-[18F]-fluoroethane (2b), 1-[18F]fluoro-3-iodopropane (2c) and 1-bromo-3-[18F]fluoropropane (2d) respectively. The biodistribution of 4 in mice showed that the mouse brain uptake of radioactivity was similar to that of [18F]-N-methylspiroperidol (1.1% of the administered dose), but the activity in bone (femur) increased with time. The kinetic distribution of compound 4 in baboon brain was similar to that of [18F]-N-methylspiroperiodol, and the striatal accumulation of radioactivity was also blocked stereoselectively by butaclamol. The ratio of striatum to cerebellum radioactivities at 3 hr after injection was 5.9. Analysis of the metabolic stability of 4 in mouse brains for 1 hr indicated that, like [18F]-N-methylspiroperidol, it is relatively stable to metabolic transformation in the central nervous system. These results suggest that compound 4 may be a useful radioligand for PET studies of the dopamine receptor in humans.

Animals↗
PubMed1987

Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat.

Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both the antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer.

Animals↗
PubMed1986

Mechanisms of action of inhibitors of prolactin secretion in GH3 pituitary cells. I. Ca2+-dependent inhibition of amino acid incorporation.

Post-transcriptional protein synthesis by GH3 cloned pituitary cells, which secrete prolactin and growth hormone, is dependent on Ca2+. The effects of antagonists of prolactin secretion were examined on overall protein synthesis in GH3 cells as a function of cellular Ca2+ depletion and restoration at varying concentrations of extracellular Ca2+. Leucine incorporation by Ca2+-depleted cells during short incubations was reduced by 80-90%. Trifluoperazine at micromolar concentrations inhibited leucine incorporation in a Ca2+-dependent manner. The extent of inhibition varied with extracellular Ca2+ concentration and was fully reversed at higher Ca2+ concentrations. Similar patterns of inhibition of leucine incorporation were observed with nifedipine, verapamil, calmidazolium, chlorpromazine, bromocriptine, ergotamine, and the (+)- and (-)-isomers of butaclamol, but dopamine, apomorphine, and chlorpromazine sulfoxide were not inhibitory. Muscarinic agonists decreased incorporation in a Ca2+-dependent manner, but lesser degrees of inhibition were obtained. Inhibitions were observed for a broad spectrum of polypeptide species, could not be explained by effects on Mg2+ availability or amino acid uptake, and were rapidly and fully reversed by Ca2+. Production of prolactin and growth hormone was decreased by secretory inhibitors to the same extent and with the same Ca2+ concentration dependence as was observed for inhibition of amino acid incorporation. It is proposed that these substances inhibit protein synthesis in GH3 cells through alterations in intracellular Ca2+ metabolism rather than through mechanisms mediated by calmodulin or dopamine receptors.

Acetylcholine↗
PubMed1985

Pharmacological differences between the D-2 autoreceptor and the D-1 dopamine receptor in rabbit retina.

The effect of dopamine receptor agonists and antagonists was studied on the calcium-dependent release of [3H]dopamine elicited by field stimulation at 3 Hz for a duration of 1 min (20 mA, 2 msec) from the rabbit retina in vitro and on adenylate cyclase activity in homogenates of rabbit retina. The relative order of potency of dopamine receptor agonists to inhibit the stimulation-evoked [3H]dopamine release was pergolide greater than bromocriptine greater than apomorphine greater than LY 141865 greater than N,N-di-n-propyldopamine greater than or equal to dopamine. The relative order of potencies of dopamine receptor antagonists to increase [3H]dopamine release was: S-sulpiride greater than or equal to domperidone greater than or equal to spiroperidol greater than metoclopramide greater than fluphenazine greater than or equal to R-sulpiride. alpha-Flupenthixol (0.01-1 microM) and (+)-butaclamol (0.01-1 microM) did not increase [3H]dopamine overflow when added alone, but they antagonized the concentration-dependent inhibitory effect of apomorphine (0.1-10 microM). These results suggest that the dopamine inhibitory autoreceptor involved in the modulation of dopamine release from the rabbit retina possesses the pharmacological characteristics of a D-2 dopamine receptor. Maximal stimulation by 30 microM dopamine resulted in a 3-fold increase in adenylate cyclase activity with half-maximal stimulation occurring at a concentration of 2.46 microM. Apomorphine and pergolide elicited a partial stimulation of adenylate cyclase activity. However, at low concentrations both compounds were more potent than dopamine. N,N-di-n-Propyl-dopamine was 30 times less potent than dopamine, and bromocriptine was unable to stimulate adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1980

The effect of typical and atypical neuroleptics on binding of [3H]spiroperidol in calf caudate.

The effect of typical and atypical neuroleptics on the binding of [3H]spiroperidol to calf caudate membranes was studied. Saturable or specific binding was defined as the difference between binding in the absence and in the presence of 1 microM d-butaclamol. Scatchard analysis revealed nonhomogeneity of the saturable sites. Inhibition constants (Ki) and IC50 values for various typical and atypical neuroleptics and for two clinically inactive butyrophenones were determined. The Ki and IC50 values of typical neuroleptics paralleled their potencies in vivo. By contrast, the binding potencies of atypical neuroleptics did not correlate with their effects in vivo. For example, the clinically active drug clozapine has an IC50 value similar to the clinically inactive butyrophenone AHR-1900. U-25, 927, another clinically inactive butyrophenone that does not increase dopamine turnover is more potent in the binding assay than perlapine, a drug that increases dopamine turnover and elevates serum prolactin levels. The most striking discrepancy between binding and properties in vivo was found for the benzamide derivatives, sulpiride and metoclopramide. These clinically active agents, which increase dopamine turnover, have much higher Ki values than the clinically inactive butyrophenones. It is concluded that binding assays with [3H]spiroperidol in calf caudate cannot account for the antidopamine effects in vivo of atypical neuroleptics.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Dopamine stimulated glycosylation of brain proteins in vitro is inhibited only partially by dopamine receptor antagonists.

Dopaminergic agonists which act on adenylate cyclase-linked dopamine receptor sites (D1-type) (dopamine, apomorphine and ADTN) induced a dose-dependent increase in the incorporation of L-fucose and D-mannose into glycoproteins of hippocampal, striatal and cortical slices of rat and mouse brain, whilst in rat liver slices dopamine failed to elicit such alterations in protein glycosylation. Testing in slices of rat hippocampus dopaminergic agonists with selective affinity to D2-receptors (bromocriptine, ergometrine) no changes in sugar incorporation into glycoproteins of rat hippocampus were observed. Dopamine stimulated L-fucose incorporation into rat hippocampal glycoproteins was inhibited to a different degree, but almost incompletely by dopamine receptor antagonists like haloperidol, D-butaclamol, promazine and alpha-flupenthixol, whilst chloropromazine and the selective D2-receptor antagonist sulpiride were without any effects. Also serotonin receptor antagonists (cinanserine) and beta-adrenergic receptor blockers (pindolol, alprenolol, practolol) failed to interfere with this dopamine action. But D,L-propranolol enhanced dopamine stimulated glycosylation of rat hippocampal proteins in an additive synergistic manner. This effect appeared to be not related to the antagonistic action of propranolol on beta-adrenergic receptor sites. From our results it is concluded that interactions with dopamine receptor sites (D1-type) is only one part of the mechanism triggering dopamine stimulated glycosylation of brain proteins in vitro.

Adrenergic beta-Antagonists↗
PubMed1984

[3H]Ro 22-1319 (piquindone) binds to the D2 dopaminergic receptor subtype in a sodium-dependent manner.

Ro 22-1319, a novel pyrroloisoquinoline compound, is a potent antipsychotic agent with low potential for extrapyramidal effects and tardive dyskinesia. In this study, the specific binding of [3H]Ro 22-1319 to the rat striatal homogenates has been examined. The binding of [3H]Ro 22-1319 was found to be critically dependent on the presence of sodium in the incubation medium. There appeared to be a single saturable binding component for [3H]Ro 22-1319 with a high affinity. The binding sites showed a stereochemical specificity for (-)Ro 22-1319, (+)butaclamol, and (alpha)flupenthixol. Ro 22-1319 and three D2 antagonistic antipsychotics (sulpiride, metoclopramide, and molindone) exerted a more potent inhibition of [3H]Ro 22-1319 binding than of [3H]spiroperidol binding, whereas other classical antipsychotics were almost equipotent at both binding sites. The requirement for sodium to detect Ro 22-1319 binding was also verified by the use of [3H] spiroperidol binding. The competition curves of Ro 22-1319, sulpiride, metoclopramide, and molindone for [3H]spiroperidol binding were shifted to the right by the omission of sodium in the incubation medium, whereas spiroperidol, chlorpromazine, and domperidone were equiactive under both conditions. These results suggest that Ro 22-1319 has a sulpiride-like property and binds to a D2 dopaminergic receptor subtype in a sodium-dependent manner. Nineteen pyrroloisoquinoline derivatives were also tested for their inhibitory effects on [3H]Ro 22-1319 and [3H] spiroperidol binding. An interesting finding was that small changes in chemical structure modulated the potency at D2 dopaminergic receptor subtypes. Thus, the compounds having a nonlipophilic functional group on the basic nitrogen (Ro 22-1319, Ro 22-3822, etc.) showed a stronger potency at [3H]Ro 22-1319 receptors whereas the compounds having a lipophilic group (Ro 22-6600, etc.) were nonselective antagonists at both [3H]Ro 22-1319- and [3H]spiroperidol-binding sites. However, all pyrroloisoquinoline derivatives including Ro 22-6600 showed a sodium dependency for [3H]spiroperidol-binding sites, indicating that the functional moiety which displays a sodium dependency may be the pyrroloisoquinoline moiety itself.

Animals↗
PubMed1983

Thermodynamic differences between agonist and antagonist interactions with binding sites for [3H]spiroperidol in rat striatum.

The characteristics of the binding of the dopamine receptor antagonist [3H]spiroperidol to rat striatal membranes were examined at six different incubation temperatures ranging from 1 degree to 37 degrees. Although the number of receptors labeled at each temperature was identical, the affinity of the receptor for [3H]spiroperidol decreased 10-fold as the incubation temperature was lowered from 37 degrees to 1 degree. The binding of [3H]spiroperidol was entropy-driven (delta S degree = +80 cal/mole-deg), endothermic (delta H degree = +10 kcal/mole), and exergonic (delta G degree = -13 kcal/mole). Qualitatively similar results were found for (+)-butaclamol, another dopamine receptor antagonist. The binding of the agonists dopamine and (+/-)-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene to sites labeled by [3H]spiroperidol in the striatum also appeared to be entropy-driven (delta S degree = +35 cal/mole-deg). In contrast to the results obtained in studies with antagonists, however, the affinity of the receptor for agonists was independent of the incubation temperature between 8 degrees and 37 degrees. Competition curves for the inhibition of [3H]spiroperidol binding by agonists became increasingly complex as the incubation temperature was lowered. The addition of GTP reduced the affinity of the receptor for agonists at all temperatures but did not simplify interpretation of these complex curves. At 1 degree there was a decrease in the affinity of the receptor for dopamine, and the effect of GTP was abolished.

Animals↗