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PubMed1981

Danazol: endocrine pharmacology and therapeutic applications.

The options for the medical management of endometriosis have been expanded by the introduction of the synthetic steroid, danazol. The results of large clinical studies suggest that danazol treatment produces significant improvement in the symptoms, signs, and laparoscopic findings of endometriosis. The original studies of the pharmacology of danazol concluded that danazol was a strong antigonadotrophin with mild androgenic effects and no other hormonal properties. Recent studies which emphasize the molecular pharmacology of danazol suggest that this steroid has direct effects on hypothalamic-pituitary function, multiple classes of steroid receptors, gonadal steroidogenesis, and endogenous steroid metabolism. These studies demonstrate that: (1) danazol prevents the midcycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); (2) danazol does not significantly suppress basal LH or FSH in gonadally intact human beings; (3) in castrated animals danazol can prevent the compensatory increase in LH and FSH; (4) danazol binds to androgen, progesterone, and glucocorticoid receptors; (5) danazol does not bind to estrogen receptors; (6) danazol binds to sex hormone-binding globulin and corticosteroid-binding globulin; (7) danazol inhibits multiple enzymes of steroidogenesis; (8) danazol increases the metabolic clearance rate of progesterone; and (9) metabolites of danazol are hormonally active. Given the complex pharmacology of danazol it is inappropriate to continue to refer to danazol as a "selective antigonadotrophin."U

Animals↗
PubMed1982

Interaction of drugs with calmodulin. Biochemical, pharmacological and clinical implications.

Calmodulin is a widely distributed, highly active, calcium-binding protein that influences a number of important biological events. Accordingly, agents that inhibit the activity of calmodulin should have profound pharmacological effects. Within the past few years, a number of compounds have been identified that inhibit calmodulin. The most potent of these described so far include certain antipsychotic drugs, smooth muscle relaxants, alpha-adrenergic blocking agents and neuropeptides. Studies of the physicochemical and structural properties of a variety of calmodulin inhibitors have shown that there are ionic and hydrophobic interactions between the drug and calmodulin. From the limited studies conducted so far, we conclude that, for a compound to inhibit calmodulin, it should carry a positive charge at physiological pH, presumably to interact with negative charges on the highly acidic calmodulin, and have hydrophobic groups, presumably to interact with lipophilic regions on calmodulin. But these two factors are not the only ones that are involved in inhibiting calmodulin, for many highly charged and highly hydrophobic agents have relatively little effect on calmodulin activity. The structural relationships between these ionic and hydrophobic regions and other, as yet identified, factors are also important. Many of the biochemical actions of the phenothiazine antipsychotic agents can be explained by the common mechanism of their binding to, and inhibiting, calmodulin. The question of whether these biochemical actions can explain their pharmacological and clinical effects is still unclear. The fundamental role calmodulin plays in biology suggests that this calcium binding protein may provide a new site for the pharmacological manipulation of biological activity. The calmodulin inhibitors described thus far hardly scratch the surface of this fertile area of research.

Antipsychotic Agents↗
PubMed1983

Dissociation of pharmacological and enzymatic activities of snake venom phospholipases A2 by modification of carboxylate groups.

The carboxylate groups in an acidic and in a basic phospholipase A2 (PLA2) enzyme, purified, respectively, from Naja naja atra and Naja nigricollis snake venoms, were modified with carbodiimide and semicarbazide. The derivatives modified at pH 3.5 and pH 5.5 had less than 1% (N. nigricollis) or 2% (N. n. atra) residual enzymatic activity, whereas 12-16% enzymatic activity remained following modification at pH 5.5 in the presence of Ca2+. In marked contrast, these derivatives retained variable, but significantly greater, levels of lethal potency, hemolytic and anticoagulant activities, and abilities to block indirectly and directly induced contractions of the diaphragm. By this modification of aspartic and glutamic acid residues we have, for the first time, obtained derivatives of PLA2 which selectively retain greater pharmacological activity relative to enzymatic activity. Previously, we had found that modification of lysine and arginine residues produced derivatives which retain enzymatic activity but show a loss of pharmacological properties. These findings suggest that some pharmacological effects of snake venom PLA2 enzymes are due to a non-enzymatic action, suggesting two distinct but perhaps overlapping active sites.

Animals↗
PubMed1984

Relationship between drug-induced increases of GABA levels in discrete brain areas and different pharmacological effects in rats.

Following the administration of two gamma-aminobutyric acid-(GABA) elevating drugs, namely aminooxyacetic acid (AOAA) and valproic acid (VPA), in rats, the relationship between the magnitude and the time course of increases in GABA levels of 11 brain regions and a number of pharmacological effects was studied. AOAA (30 mg/kg i.p.) caused significant GABA increases in all brain areas but the degree and time course of these increases showed considerable variation from region to region. The most marked effects were seen in the olfactory bulb, frontal cortex and hippocampus, in which maximum GABA elevations of 100-200% were reached 4-6 hr after AOAA injection. In all the other regions studied (corpus striatum, thalamus, hypothalamus, superior and inferior colliculus, substantia nigra, pons, medulla, cerebellum), increases in GABA were less marked and, at least in part, maximum increases (30-60% over control) were already reached by 1-2 hr. In contrast to AOAA, VPA (200 mg/kg i.p.) produced significant increases in GABA levels only in the cortex, olfactory bulb, corpus striatum, hypothalamus and cerebellum, maximum effects (15-35%) being already reached 5-30 min after VPA administration. As regards pharmacological effects, AOAA caused marked hypothermia, which was maximal by 1 hr and could be reversed by increasing ambient temperature, whereas effects of VPA on body temperature were only moderate. On the other hand, both drugs exerted an almost equal, pronounced antinociceptive effect in the hot plate test. Anticonvulsant efficacy was evaluated in three seizure models, namely the maximal (tonic extension) electroconvulsive threshold, and seizures induced by pentylenetetrazol and 3-mercaptopropionic acid. Anticonvulsant effects of AOAA against electroshock and pentylenetetrazol could only be determined 1 hr after injection, at which time AOAA was inactive against 3-mercaptopropionic acid-induced seizures. VPA proved to be clearly superior to AOAA in both anticonvulsant potency and duration of action. The marked differences in functional effects between VPA and AOAA could not be related to their differential effects on GABA levels in discrete brain regions. The data thus suggest that measurement of total GABA in brain regions without consideration of the compartmentalization of the neurotransmitter is only of limited value to use in an attempt to correlate elevation of GABA levels and pharmacological effects.

Aminooxyacetic Acid↗
PubMed1989

Further studies on the pharmacologic effects of the 7-hydroxy catabolite of methotrexate in the L1210 murine leukemia cell.

This paper describes studies that further explore the pharmacologic activity of the 7-hydroxy catabolite of methotrexate (7-OH-MTX). A 3-hr exposure of L1210 leukemia cells to 100 microM 7-OH-MTX produced negligible suppression of cell growth despite the build-up of intracellular polyglutamyl congeners to levels 2.7 times greater than the dihydrofolate reductase (DHFR) binding capacity. There was no evidence for direct inhibition of DHFR under these conditions based upon measurements of cellular tetrahydrofolate cofactor and dihydrofolate levels, nor was there suppression of [3H]deoxyuridine incorporation into DNA or [14C]formate incorporation into purines. When the interval of exposure to 100 microM 7-OH-MTX was increased to 6 hr, cell growth was inhibited by 60% and there was mild (approximately 50%) inhibition of purine and thymidylate biosynthesis associated with a small increase in cellular dihydrofolate and a small decline in cellular tetrahydrofolates. Consistent with weak inhibition of DHFR was the absence of significant binding of 7-OH-MTX polyglutamates to DHFR as assessed by gel filtration of cell extracts. Mild direct inhibition of purine biosynthetics by 7-OH-MTX- or MTX-polyglutamyl congeners was demonstrated based upon inhibition of [14C]formate incorporation into purines in cells pretreated with fluorodeoxyuridine so as to prevent tetrahydrofolate cofactor depletion or dihydrofolate polyglutamate build-up. Effects of a 6-hr exposure of cells to 100 microM 7-OH MTX on cell growth were reversed completely by 10 microM leucovorin; effects on cells containing comparable levels of MTX polyglutamyl congeners were unaffected by leucovorin. These studies demonstrate very weak inhibition of L1210 leukemia cell growth and purine, pyrimidine and tetrahydrofolate synthesis by the polyglutamyl congeners of 7-OH-MTX. The data suggest that effects of 7-OH-MTX polyglutamates on folate-requiring enzymes are not likely to play an important role in moderate-dose MTX regimens. However, pharmacologic activity may be expressed in high-dose MTX protocols when high blood levels of 7-OH-MTX are sustained over long intervals to the extent to which polyglutamate congeners accumulate in tumor cells and add to the much more potent inhibitory effects of MTX polyglutamates already present. Pharmacologic activity, however, would be diminished, if not completely reversed, by the concurrent administration of leucovorin.

Animals↗
PubMed1996

Selective pharmacological inhibition of distinct nitric oxide synthase isoforms.

Nitric oxide (NO) is produced in physiological and pathophysiological conditions by three distinct isoforms of NO synthase (NOS): endothelial NOS (ecNOS), inducible NOS (iNOS), and brain NOS (bNOS). Selective inhibition of iNOS may be beneficial in various forms of shock and inflammation, whereas inhibition of bNOS may protect against neuroinjury. This article surveys the enzymatic mechanism of NO production, lists the strategies and pharmacological tools for selective inhibition of distinct NOS isoforms, and considers the side-effects of the various approaches. Selective inhibition of NOS isoforms is achieved by: (a) targeting the differential co-factor (calmodulin or tetrahydrobiopterin) requirement of various NOS isoforms, and NOS; (b) targeting the differential substrate requirements of cells expressing various isoforms of NOS (L-arginine uptake blockers or arginase); (c) the use of pharmacological agents that are selectively taken up by cells expressing various isoforms of NOS (7-nitroindazole); or (d) developing pharmacological NOS inhibitors with isoform specificity. The amino acid-based NOS inhibitor, NG-nitro-L-arginine, shows a preference for ecNOS and bNOS over iNOS, whereas L-N6-(1-iminoethyl)lysine is selective for iNOS over bNOS. Certain non-amino acid-based small molecules, such as aminoguanidine and certain S-alkylated isothioureas, also express selectivity towards iNOS and have anti-inflammatory and anti-shock properties. 7-nitroindazole, a bNOS-selective inhibitor, protects in central nervous system injury. Clearly, there are a number of distinct approaches that are worthy of further research efforts in order to achieve even more selective targeting of various NOS isoforms

Animals↗
PubMed1979

Two pharmacologically distinct histamine receptors mediating membrane hyperpolarization on identified neurons of Aplysia californica.

Two distinct hyperpolarizing responses are produced when histamine is iontophoretically applied onto the somal membranes of identified neurons within the cerebral ganglion of Aplysia: a biphasic response consisting of a rapid component (less than 5 sec) usually superimposed upon a slowly developing component; or a monophasic slowly developing response 5-20 sec in duration. The reversal potential values for the fast (typically -65 mV) and the slow (typically -89 mV) responses, and their shift to new values when the external potassium or chloride concentrations were altered, revealed that the fast and slow potentials are produced predominantly by conductance increases to chloride and potassium ions, respectively. The effects of histamine H1- and H2-receptor agonists and antagonists were studied to characterize the pharmacological properties of histamine receptors mediating these two ionically dissimilar hyperpolarizing responses. The slow potassium-dependent hyperpolarization could be mimicked by several histamine analogues; the most potent tested were the H1-receptor agonist, 2-methylhistamine, and the H2-receptor agonist, 4-methylhistamine. Neither of these agents mimicked the fast chloride-dependent histamine response. The slow potassium-dependent responses induced by histamine or histamine agonists were completely and reversibly blocked by the H2-receptor antagonist, cimetidine. By contrast, the slow potassium-dependent hyperpolarizations produced by iontophoretically applied acetylcholine or by dopamine to the same neurons were unaffected by cimetidine. Other H1 and H2 antagonists tested were either ineffective, or only partially blocked the slow hyperpolarizations in a non-selective manner. The fast chloride-dependent hyperpolarizations were not selectively antagonized by any of the H1 or H2 reagents tested, although they were effectively suppressed by tubocurarine and strychnine. These data indicate that two pharmacologically distinct histamine receptors mediate potassium- and chloride-dependent hyperpolarizations in Aplysia neurons. Neither of these receptors, however, could be classified as strictly H1 or H2 according to criteria presently used in non-neuronal tissues. The selectivity and reversibility of cimetidine indicate that this particular antihistaminic could be a valuable pharmacological tool for defining putative histaminergic synapses in Aplysia and perhaps other nervous systems.

Acetylcholine↗
PubMed1985

The glycine receptor in the mutant mouse spastic (spa): strychnine binding characteristics and pharmacology.

There is a marked deficit in the binding of the glycine receptor antagonist strychnine to the CNS of the mutant mouse spastic. The characteristics and pharmacology of [3H]strychnine binding to washed homogenates of spastic and littermate control spinal cord and brainstem were investigated to determine the nature of this defect. The maximal binding of [3H]strychnine to spastic homogenates is approximately 20% the value obtained from littermate control homogenates; the affinity of [3H]strychnine binding is approximately 25% lower than littermate control values. The pharmacology of [3H]strychnine binding has the same rank order of potency in spastic and littermate control mice; however, there are small differences in the potency of several compounds in spastic vs littermate control animals. These results indicate that the glycine receptor alteration seen in the spastic mutant mouse is primarily due to a decrease in receptor number. They also suggest that the pharmacological characteristics of the glycine receptor in spastic are different from littermate control. The data do not permit a distinction between whether the strychnine binding sites found in spastic represent the same population seen in littermate control animals or are a subpopulation that is spared by the mutation.

Animals↗
PubMed1992

Further pharmacological characterization of [3H]idazoxan binding sites in rat brain: evidence for predominant labeling of alpha 2-adrenergic receptors.

In addition to binding to alpha 2-adrenergic receptors, the antagonist [3H]idazoxan has been reported to bind to non-adrenergic sites in a number of tissues and species. In the present study, the pharmacological nature of [3H]idazoxan binding sites in rat brain slices has been examined using radioligand binding and autoradiographic techniques. In Na2KHPO4 buffer, four drugs with high affinity for alpha 2-adrenergic binding sites were potent inhibitors of [3H]idazoxan binding, with the rank order of potency being RX821002 greater than phentolamine greater than yohimbine greater than (-)epinephrine. Non-linear regression analysis resolved all competition curves into two components, with the high affinity site representing the majority of total [3H]idazoxan binding. In autoradiographic studies performed in Na2KHPO4 buffer, all alpha 2-selective ligands displaced greater than or equal to 75% of total [3H]idazoxan binding to most brain regions. These findings indicate that the major component of [3H]idazoxan binding was to sites that are alpha 2-adrenergic in nature. [3H]Idazoxan binding was also examined in glycylglycine buffer. In contrast to binding in Na2KHPO4 buffer, the proportion of low affinity sites was significantly increased in glycylglycine buffer. Autoradiographic studies confirmed these findings. These pharmacological data are consistent with our previously reported conclusions that, under appropriate assay conditions, [3H]idazoxan predominantly labels alpha 2-adrenergic binding sites in rat brain. These sites are widely distributed and have pharmacological characteristics consistent with those previously reported for alpha 2A-adrenergic receptors.

Adrenergic alpha-Antagonists↗
PubMed1993

The effects of pharmacologic doses of 2-deoxy-D-glucose on local cerebral blood flow in the awake, unrestrained rat.

Previous studies on the effects of acute insulin-induced hypoglycemia on cerebral blood flow (CBF) have resulted in conflicting results. An alternate approach to the study of glucoprivation is the administration of pharmacologic doses of the glucose analogue, 2-deoxy-D-glucose (2-DG). 2-DG is transported across the blood-brain barrier into brain tissue where it is phosphorylated to 2-deoxy-D-glucose-6-phosphate (2-DG-6-P) but not metabolized further. The 2-DG-6-P accumulates and inhibits the conversion of glucose-6-phosphate to fructose-6-phosphate, thus blocking glycolysis and glucose metabolism. In the present study we have employed the [14C]iodoantipyrine method to examine the effects of a pharmacologic dose (500 mg/kg) of 2-DG on local cerebral blood flow (lCBF) in 29 regions of the brain in conscious, unrestrained, adult male rats. The 2-DG treatment raised arterial plasma glucose levels from 8 to 17 mM without affecting arterial blood pO2, pCO2, or pH but increased lCBF in most brain regions examined. The largest increases were in the cerebral cortex, basal ganglia, and thalamic nuclei (+65 to +157%). Smaller increases were found in most structures of the limbic system, brainstem, and white matter, and no changes in lCBF were seen in the cerebellar cortex and ventral medial hypothalamus. The results indicate that cerebral glucoprivation produced by pharmacological doses of 2-deoxyglucose is accompanied by substantial increase in blood flow in most regions of the brain.

Animals↗
PubMed1995

Cool perfusion solutions for skin flaps: a new mixture of pharmacological agents which improves skin flap viability.

This study tested the hypotheses that perfusion of cooled skin flaps with established organ preservation solutions improves their viability and that this improvement can be further enhanced by pharmacological manipulation. Rabbit epigastric skin flaps were perfused with different solutions before explantation and stored at 8 degrees C for 6 days. In the first part of the experiment, flap viability was assessed 7 days after reperfusion of the flap via microvascular anastomoses. The different solutions were heparinised blood, University of Wisconsin solution, two of its modifications, EuroCollins solution and a pharmacological mixture containing phosphoenolpyruvate, desferrioxamine, nitrendipine, dextran 70 and a platelet-aggregating factor receptor antagonist (WEB 2170). In the second part, biochemical parameters of skin were measured at various reperfusion times. Adenosine triphosphate (ATP), reduced glutathione (GSH), myeloperoxidase (MPO) and tissue water were assayed at 0, 1, and 24 h after reperfusion. In addition, plasma thromboxane (TXB2) was measured at 0, 30 and 60 minutes after reperfusion. The viability of flaps perfused with the mixture (81%) was significantly higher than that of any of the other groups (39% for controls, 38% for EuroCollins, 13% for UW solution, 27% and 31% for its modifications). ATP levels after reperfusion were higher in the mixture group than in UW-perfused group. GSH levels in the mixture group were also higher than in the UW group, indicating higher level of protection against oxidative stress during reperfusion. There were no differences in MPO levels. Thromboxane levels associated with UW-perfused flaps were significantly higher than those associated with any other perfusion solution. In conclusion, perfusion of a mixture of pharmacological agents targeting specific aspects of ischaemia/reperfusion injury improved the viability of skin flaps stored in the cold for 6 days, whereas standard organ preservation solutions failed to affect significantly skin flap survival.

Adenosine↗
PubMed1984

Antifertility activity and general pharmacological properties of ORF 13811: a synthetic analog of zoapatanol.

ORF 13811, a synthetic analog of zoapatanol, was evaluated in a variety of in vivo and in vitro biological test systems to determine antifertility and uterotonic activity as well as its general pharmacological profile. ORF 13811 is a potent antifertility agent after oral administration in a number of animal species including mice, rats, guinea pigs, dogs and baboons. The single oral ED50 for contragestational activity in the pregnant guinea pig (day 22), mouse (day 16) and rat (day 16) is in the range of 6 to 10 mg/kg. In pregnant beagle dogs, a dose-related contragestational effect was obtained within several days after oral administration of ORF 13811 in the dosage range of 10 to 30 mg/kg. ORF 13811, when administered to pregnant baboons, caused dose-related vaginal bleeding and evacuation of uterine contents within 3 days following treatment with oral doses of 40 to 60 mg/kg. Serum progesterone levels were decreased in baboons and the degree of reduction correlated with contragestational activity. ORF 13811 was also effective in inhibiting implantation in mice, rats and hamsters, but required higher dose levels than those of the post-implantive treatments. In vitro uterotonic properties of ORF 13811 were demonstrated by its ability to induce contraction of uterine strips obtained from female guinea pigs at two different reproductive stages (day 15 of the estrous cycle and day 22 of pregnancy). In these preparations ORF 13811 was approximately 1/30 to 1/50th as potent as PGF2 alpha. In a series of pharmacological tests, ORF 13811 was found to possess slight sedative properties but was devoid of activity on pulmonary, gastrointestinal, and immune systems as well as in a number of biochemical tests, data not reported here. However, in cardiovascular studies, ORF 13811 appears to possess a vasoconstrictor profile in the dog, monkey and baboon as indicated by an increase in mean arterial blood pressure as well as total peripheral and regional vascular resistances. The in vitro pharmacological profile of ORF 13811 was examined in myocardial tissue and vascular smooth muscle test systems and compared to PGF2 alpha. ORF 13811 was found to contract rat aortic strips, 15 times less potent than PGF2 alpha. The compound had no direct effect on isolated guinea pig atria or papillary muscle. In summary, ORF 13811 is a potent orally active antifertility agent characterized primarily as a contractor of uterine and vascular smooth muscle.

Animals↗
PubMed1977

Pharmacologic response to pentobarbital in actively immunized mice.

Mice were placed on an immunization schedule known to result in the production of antibodies directed against a variety of barbiturates (antibody binding capacity = 2.71 pmole 3H-phenobarbital bound/ml undiluted serum). The pharmacologic response to barbiturate in these actively immunized mice and suitably treated controls was investigates using rotarod apparatus for monitoring CNS depression. It was found that the response to pentobarbital in actively immunized mice was decreased, as reflected by an increase in the time the mice remained on the rotarod and a shift of the dose--response curve to the right. The decreased pharmacologic response to pentobarbital was not the result of changes in levels of the hepatic drug metabolism components. Furthermore, the alteration of pharmacologic response in actively immunized mice was selective for barbiturate and did not modify the ataxia produced by administration of another depressant agent, ethanol.

Aminopyrine N-Demethylase↗
PubMed1988

Comparison of the pharmacological characteristics of [3H]raclopride and [3H]SCH 23390 binding to dopamine receptors in vivo in mouse brain.

In vivo binding of the benzamide derivative [3H]raclopride was studied in mouse brain. The binding was saturable, reversible and stereospecific. Non-specific binding was 5-15% of the total binding. Pharmacological characterization of the binding indicated labelling of dopamine D2 receptors since the binding was potently inhibited by compounds with high affinity for this receptor in vitro. On the other hand, compounds with low affinity in vitro i.e., dopamine D1-selective compounds were weak or inactive as inhibitors of [3H]raclopride binding. A comparison of the pharmacological characteristics of [3H]raclopride and [3H]SCH 23390 binding in vivo indicated that compounds with selectivity in vitro retained this selectivity in vivo. Thus, spiroperidol, haloperidol, 1-sulpiride, clebopride, LY 171555 and (-)-NPA ((-)-N-propyl-norapomorphine) were D2 selective while SCH 23390, SKF 38393 and SKF 75670 were D1 selective. Clozapine, tilozepine, cis-flupentixol, chlorpromazine and butaclamol were non-selective both in vitro and in vivo. However, a few compounds changed profile in vivo compared to in vitro. Thus, fluperlapine and fluphenazine had a dual D1-D2 receptor profile in vitro but were D1- or D2-selective in vivo, respectively. Pergolide and molindone which were D2-selective in vitro both had a dual D1-D2 receptor profile in vivo. In conclusion, [3H]raclopride, in vivo, selectively labels the dopamine D2 receptor. Comparison of the pharmacological characteristics of [3H]raclopride and [3H]SCH 23390 binding in vivo supported the that the dopamine D1 receptor is an important target for a variety of neuroleptics, especially of the clozapine type. This may indicate that blockade of the dopamine D1 receptor conveys antipsychotic action.

Animals↗
PubMed1989

Two pharmacological classes of quisqualate-induced electrical responses in rat retinal ganglion cells in vitro.

The pharmacological properties of steady state responses elicited by the excitatory amino acid agonists quisqualate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) have been examined in isolated rat retinal ganglion cells with patch electrodes. Based upon testing retinal ganglion cells with both agonists at saturating concentrations (30 microM for quisqualate and 60 microM for AMPA), these neurons can be grouped into three different categories: (a) type I cells, in which AMPA steady state responses were larger than those induced by quisqualate; (b) type II cells, in which quisqualate steady state responses were larger than or equal to those produced by AMPA; and (c) type III cells, in which neither AMPA nor quisqualate elicited responses. Regardless of cell type (I or II), AMPA responses were substantially inhibited by the antagonists kynurenate (750 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM). In contrast, the effects of these antagonists on quisqualate responses varied depending on the cell type, with both kynurenate and CNQX being more effective in type II than in type I cells. Based upon further pharmacological manipulations, it is proposed that quisqualate-induced steady state responses in retinal ganglion cells are divisible into two pharmacological classes that exist in varying proportions in these cells in vitro.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

Pharmacology of muscarinic acetylcholine receptor subtypes (m1-m5): high throughput assays in mammalian cells.

Based on the ability of many receptors to amplify NIH 3T3 cells, we developed a high throughput assay of cloned receptor pharmacology. In this assay, receptors are transiently co-expressed with the marker enzyme beta-galactosidase. Receptors that induce cellular proliferation select and amplify the cells that also express the marker, thus the ability of ligands to alter receptor activity are reported as changes in enzyme activity. We used this assay to evaluate the pharmacology of agonist and antagonist ligands for five cloned human muscarinic receptor subtypes (m1-m5). When cells were transfected with subtypes that prefer the G-protein Gq (m1, m3, m5) robust increases in enzyme activity were observed. The subtypes that prefer Gi (m2 and m4) only induced beta-galactosidase when co-expressed with a chimera between the G-proteins Gq and Gi (Gq-i5). Overall, the rank-order of potency and intrinsic activity of most of the tested ligands were in remarkably good agreement with earlier results using cloned cell lines and isolated tissues. These data demonstrate that a high throughput colorimetric assay performed in 96-well plates can be used to evaluate subtle differences the pharmacology of ligands for cloned muscarinic receptor subtypes.

Binding, Competitive↗
PubMed1996

Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem.

The BZ1 (omega 1)-selective compound, zolpidem, is a clinically effective hypnotic drug with a pharmacological profile which differs from those of benzodiazepine anxiolytics and hypnotics. Zaleplon (CL 284,846) has recently been described as a hypnotic agent which also has BZ1 (omega 1) receptor selectivity. The pharmacological effects of zolpidem and zaleplon were therefore compared in mice and rats. Both drugs blocked tonic convulsions induced in mice by pentylenetetrazole and electroconvulsive shock and clonic convulsions induced by isoniazid. Zaleplon was more potent than zolpidem but the maximal effect of zolpidem for increasing the latency to isoniazid-induced convulsions was greater than that of zaleplon. Little tolerance developed to the anticonvulsant effect of zaleplon against isoniazid-induced seizures following twice daily administration of 10 or 30 mg/kg for 10 days. Both compounds reduced locomotor activity and produced motor deficits in the rotarod and loaded grid tests in mice. However, while zaleplon produced all three effects at similar doses, zolpidem showed the greatest potency for reducing locomotion. Zaleplon and zolpidem also decreased locomotion and produced a rotarod deficit in rats. Again, the difference between the doses giving rise to these two effects was greater for zolpidem than for zaleplon. In a drug discrimination procedure using rats trained to discriminate a dose (5 mg/kg) of chlordiazepoxide, zaleplon produced partial substitution for chlordiazepoxide at doses which greatly reduced response rates. These results show that zaleplon and zolpidem have similar pharmacological profiles, presumably related to their BZ1 (omega 1) receptor selectivity. However, the difference between doses producing motor deficits (rotarod, loaded grid) and those giving rise to other effects (anticonvulsant, decreased locomotion) was greater for zolpidem than for zaleplon. This difference may be related to a greater in vivo intrinsic activity of zolpidem as indicated by the different efficacies of the two drugs to antagonise isoniazid-induced convulsions.

Acetamides↗
PubMed1983

Effects of norepinephrine and other pharmacological agents on prostaglandin E2 release by rabbit and bovine irides.

We have investigated: (a) synthesis and release of prostaglandin E2 (PGE2) and the effects of norepinephrine (NE) and other pharmacological agents thereon in rabbit and bovine irides; (b) the role of Ca2+ and the type of adrenergic receptors involved in PGE2 release by rabbit iris; (c) the structural requirement for catecholamine stimulation of PGE2 release by rabbit iris. Irides were incubated in Krebs-Ringer buffer (pH 7.4) in the absence and presence of pharmacological agents at 37 degrees C for 20 min. PGE2 in the medium was quantitated by radioimmunoassay; or by means of radiometric and chromatographic methods when [1-14C]-arachidonic acid was employed as precursor. Analysis of tissue PGE2 at the start of incubation revealed that rabbit and bovine irides contained about 185 and 18 ng/g tissue, respectively. During 15 min of incubation the release of PGE2 from rabbit and bovine irides was approximately 1100 and 14 ng/g tissue, respectively. We found that the rabbit iris and iris microsomes synthesize PGE2, both from endogenous and exogenous arachidonate pools, at a rate several times as high as that of bovine. Release of PGE2 by irides from both species is time-dependent; the stimulatory effects of NE on PGE2 release by irides from rabbit are more pronounced than those of the bovine; and the NE-induced release of PGE2 was abolished by low concentrations of indomethacin (1.5 microM). Synthesis and the effect of NE on PGE2 release by irides from albino and pigmented rabbit eyes are similar. It is concluded that the differences observed in the synthesis of PGE2 and the effect of NE on its release by rabbit and bovine irides are due to species differences. NE stimulation of PGE2 release by rabbit iris is probably mediated through alpha-adrenoceptors and maximal adrenergic stimulation requires the presence of Ca2+. Ca2+-ionophore A23187 significantly increased PGE2 release. These data suggest that the control step in PG synthesis, that is the release of free arachidonate from membrane phospholipids, could be involved in the NE-induced PG synthesis in this tissue. The structural studies revealed that both the catechol nucleus and the ethylamine polar-side chain are required for catecholamine activation of PG release by the rabbit iris. Thus normetanephrine significantly stimulated PGE2 release by the rabbit iris and iris microsomes; 3-methoxy, 4-hydroxy mandelic acid had no effect; and catechol at 50 microM inhibited PGE2 release by more than 50%. Catecholamines and adrenergic drugs are routinely employed therapeutically to lower intraocular pressure in the eye, and a catecholamine-induced increase in PG synthesis may play a significant role in mediating the pharmacological effects of these therapeutic agents.

Animals↗