Salbutamol: A new, selective β-adrenoceptive receptor stimulant

1. Salbutamol is a beta-adrenoceptive receptor stimulant. Its pharmacological actions are reduced or abolished by beta-receptor antagonists.2. In anaesthetized animals, salbutamol, given intravenously, was slightly less active than isoprenaline in preventing spasm of bronchial smooth muscle but was considerably less active as a cardiac stimulant and vasodepressor substance. Its duration of action was about 2 to 3 times that of isoprenaline.3. Salbutamol given by mouth or aerosol to conscious guinea-pigs, greatly diminished bronchospasm caused by inhalation of acetylcholine. By mouth, salbutamol was more active and had a longer duration than isoprenaline or orciprenaline without affecting heart rate. By aerosol, salbutamol was approximately 10 times as active as isoprenaline and 100 times as active as orciprenaline. Its duration of action was much longer than that of isoprenaline or orciprenaline. Only isoprenaline produced an increase in heart rate by the aerosol route.4. On isolated guinea-pig trachea salbutamol had about 1/10 the activity of isoprenaline, on isolated atria about 1/2000.     

Clinical investigation of an antagonist at α- and β-adrenoceptors-AH 5158A

1. The alpha- and beta-adrenoceptor blocking action of AH 5158A was investigated in man using the veins of the hand, the arterial bed of the forearm, and certain responses of the circulation as a whole.2. In the veins, locally infused AH 5158A resulted in specific and competitive antagonism of the constrictor response to locally infused noradrenaline and of the dilator response to isoprenaline.3. Brachial artery infusions of AH 5158A resulted in competitive antagonism of the arterial blood flow changes produced by local infusions of noradrenaline and isoprenaline.4. Systemic infusion of AH 5158A (0.5-0.9 mg/kg) produced clear blockade of the heart rate response to systemic infusion of isoprenaline. It also attenuated the response to exercise at 80 watts for 4 min; mean arterial pressure during exercise was reduced by 16% and heart rate by 18%. Blockade lasted at least 1 hour.5. AH 5158A caused small changes in arterial pressure and heart rate at rest supine, but had no effect on the response of pressure and rate to tilting.     

A study of the β-adrenergic receptors in rat kidneys

Dichloroisoprenaline (1 mg), injected intramuscularly into the rat, retarded the elimination of water and retained sodium, depressing both glomerular filtration rate and renal blood flow. A dose of 4 mg had a similar but more intense action. These actions of dichloroisoprenaline resembled those of 2 or 4 μg of (±)-isoprenaline given subcutaneously. Dichloroisoprenaline and (±)-isoprenaline summed in salt retaining effect but competed in renal vascular action. 2-Isopropylamino-1-naphth-2'-ylethanol hydrochloride (nethalide, 1 mg intramuscularly) was without action during water diuresis. A dose of 4 mg inhibited solely the excretion of water. Nethalide (1 mg) completely antagonized the antidiuretic and vascular actions of 2 μg of (±)-isoprenaline; antagonism of the salt retention caused by (±)-isoprenaline was less complete. A dose of 4 mg of nethalide antagonized both the salt retaining and the vascular actions of 4 μg of (±)-isoprenaline.     

β-Adrenoceptor antagonist activity of 3-methoxyisoprenaline

1. The beta-adrenoceptor antagonist activity of 3-methoxyisoprenaline, the O-methylated metabolite of isoprenaline, was studied on isolated driven atrial strip and tracheal chain preparations of the guinea-pig and on the hind limb blood flow of the dog.2. On both the atrial strip and tracheal chain preparations the blockade of responses to isoprenaline fulfilled the criteria for simple competitive inhibition.3. 3-Methoxyisoprenaline decreased the vasodilator response to isoprenaline in the dog hind limb, but did not affect the response to noradrenaline.4. 3-Methoxyisoprenaline had about 1/3,700 of the potency of propranolol as a beta-adrenoceptor antagonist on the tracheal chain preparation, 1/1,000 on the atrial strip preparation and less than 1/400 on the hind limb blood flow.5. The antagonist activity of 3-methoxyisoprenaline showed a slight specificity for cardiac beta-adrenoceptors, being 4.3 times more active on guinea-pig atria than on trachea.6. Although 3-methoxyisoprenaline antagonized the actions of isoprenaline in the three preparations, its activity was extremely weak. It is unlikely that the formation of 3-methoxyisoprenaline from isoprenaline, administered therapeutically, could lead to beta-adrenoceptor blockade.     

Pharmacological properties of ββ-dimethylacryloylcholine and some other β-substituted acryloylcholines

The mammalian pharmacology of a new naturally occurring ester of choline, ββ-dimethylacryloylcholine (DMAC), has been studied, mainly in the cat, together with that of two synthetic β-substituted acryloylcholines, crotonoylcholine and pent-2-enoylcholine. Comparisons have been made with the reduced form of DMAC, isovalerylcholine, with another naturally ocurring β-substituted acryloylcholine, murexine (urocanoylcholine), and with suxamethonium. DMAC has been shown to be a ganglion stimulating and neuromuscular blocking agent generally similar, in potency and properties, to murexine. It is also a powerful respiratory stimulant. The other unsaturated esters behaved similarly but were less potent.     

The β-adrenergic blocking and pressor actions of isoprenaline in the cat

In the anaesthetized cat a single, large, intravenous dose of (—)-isoprenaline reversibly blocked the depressor properties of isoprenaline. Further large doses then caused monophasic rises in blood pressure, which were similar in rate of onset and duration to those produced by adrenaline and noradrenaline. This pressor effect was not due to an increase in cardiac output, but the main cause was vasoconstriction in skeletal muscle. The responses to isoprenaline, adrenaline and noradrenaline were compared, both before and after the blocking dose of isoprenaline. Isoprenaline prevented or antagonized the potentiation of the pressor effects of adrenaline and noradrenaline by cocaine. The pressor effect was blocked but not reversed by ergotamine and tolazine, which block sympathetic α-receptors. It is suggested that isoprenaline in large doses has two actions on the vascular system of the cat: a blockade of the sympathetic β-receptors and an excitation of α-receptors.     

The effects of a new α- and β-adrenoceptor antagonist (AH5158) upon the general and coronary haemodynamics of intact dogs

AH5158, a salicylamide derivative, said to be a blocker of alpha- and beta-adrenoceptors, has been studied in intact anaesthetized dogs. At a dose of 2.5 mg/kg intravenously, the drug increased cardiac output and caused a late fall in mean systemic and pulmonary arterial pressure. Coronary sinus flow increased, as did cardiac oxygen extraction. External cardiac efficiency decreased. Blood glucose and non-esterified fatty acid values increased, but cardiac extraction of these did not change.     

Association of β-agonists with corresponding β2- and β1-adrenergic pentapeptide sequences

Synthesized β₁- and β₂-pentapeptide sequences corresponding to published adrenoceptor transmembrane activation site subtypes were investigated in vitro for selectivity in association for drug ligands of known selectivity. Both nuclear magnetic resonance spectroscopy and molecular mechanics demonstrated that structural differences among the corresponding pentapeptide activation-site sequences can explain agonist selectivity. Results suggest the agonists bind across the activation site loop on the second transmembrane α-helix by dipole/dipole interactions between a ligand and the peptide. Since electrostatic interactions within the membrane may determine the rate of intercellular ion flux, agonist association across the activation site sequence could thereby decrease electrostatic resistance to positive ion flux into the cell. Interactions between the peptides and the ligands may provide insight into the structures and mechanisms involved in association of ligands for the identical sequences on the β-adrenoreceptors.     

Further studies regarding the structure activity relationships of β-adrenoceptor antagonists

1. The ortho (M66,527) and para (M66,368) analogues of 1-t-butylamino-3-(methoxyphenoxy)-2-propanol and para substituted tertiary butylphenoxy-1-N-isopropylamine-3 propanol-2 oxalate acid (L8429) were tested in dogs for their beta-adrenoceptor blocking activity.2. M66,527, which contains a methoxy group in the ortho position of the benzene ring, was found to be comparable to propranolol in blocking cardiac and peripheral vascular responses to isoprenaline. Like propranolol, M66,527 was more potent on peripheral receptors.3. Transference of the methoxy group to the para position (M66,368) reduced the overall potency; however, this compound was found to be relatively cardioselective in that it was 2 to 3.6 times more active in blocking cardiac responses to isoprenaline.4. The cardioselective properties of the short chain para methoxy substituent were less than those reported for compounds with longer para substitutions (i.e. practolol, para oxprenolol and para alprenolol).5. L8429, with a tertiary butyl group in the para position, was a weak beta-adrenoceptor antagonist without cardioselective properties. A longer, less bulky n-butyl group may provide for a more potent and selective antagonist.6. The results support the view that the size and site of the substituent on the benzene ring may be of importance in determining the cardioselective potency of beta-adrenoceptor antagonists.     

1-Isopropylamino-3-(4-indanoxy)-2-propanol HCl: A potent β-adrenoceptor antagonist

1. The beta-adrenoceptor blocking activity of 1-isopropylamino-3-(4-indanoxy)-2-propanol HCl (USVC 6524) was determined in the anaesthetized dog, the isolated rat uterus and the isolated guinea-pig tracheal strip.2. USVC 6524 inhibited the positive inotropic, positive chronotropic and vasodilator responses to isoprenaline in the dog in a dose of 10 mug/kg and higher. On the basis of comparative pA(2) values, USVC 6524 is approximately 10 times more potent as a beta-adrenoceptor antagonist than propranolol.3. Cardiac depressant effects produced by USVC 6524 were relatively mild and occurred only after the onset of a strong beta-adrenoceptor blockade.4. USVC 6524 also blocked beta-adrenoceptors in the isolated rat uterus and guinea-pig tracheal spiral strip.     

Targeting interleukin-13 receptor α2 (IL-13Rα2) for glioblastoma therapy with surface functionalized nanocarriers

Despite surgical and therapeutic advances, glioblastoma multiforme (GBM) is among the most fatal primary brain tumor that is aggressive in nature. Patients with GBM have a median lifespan of just 15 months when treated with the current standard of therapy, which includes surgical resection and concomitant chemo-radiotherapy. In recent years, nanotechnology has shown considerable promise in treating a variety of illnesses, and certain nanomaterials have been proven to pass the blood–brain barrier (BBB) and stay in glioblastoma tissues. Recent preclinical research suggests that the diagnosis and treatment of brain tumor is significantly explored through the intervention of nanomaterials that has showed enhanced effect. In order to elicit an antitumor response, it is necessary to retain the therapeutic candidates within glioblastoma tissues and this job is effectively carried out by nanocarrier particularly functionalized nanocarriers. In the arena of neoplastic diseases including GBM have achieved great attention in recent decades. Furthermore, interleukin-13 receptor α chain variant 2 (IL13Rα2) is a highly expressed and studied target in GBM that is lacked by the surrounding environment. The absence of IL13Rα2 in surrounding normal tissues has made it a suitable target in glioblastoma therapy. In this review article, we highlighted the role of IL13Rα2 as a potential target in GBM along with design and fabrication of efficient targeting strategies for IL13Rα2 through surface functionalized nanocarriers.     

Inhibition of rabbit intestine mediated by α- and β-adrenoceptors

1. The effects of some alpha- and beta-adrenoceptor agonists and antagonists were studied on isolated segments of rabbit intestine in an attempt to characterize the two types of inhibitory response produced by sympathomimetic amines.2. Phenylephrine, an alpha-adrenoceptor agonist, produced an inhibition of rapid onset, from which recovery occurred despite the continued presence of the drug. On washout there was an overshoot in contraction height. Isoprenaline, a beta-adrenoceptor agonist, produced an inhibition of slow onset which was maintained throughout the presence of the drug and there was no overshoot on washout.3. Adrenaline resembled phenylephrine more closely than it resembled isoprenaline, in that it showed more affinity for alpha-adrenoceptors, whereas noradrenaline, and the transmitter released on periarterial nerve stimulation, behaved more like isoprenaline, although both types of receptor were affected.4. Adenosine-5'-triphosphate produced an inhibition resembling that produced by an alpha-adrenoceptor agonist, whereas the dibutyryl analogue of cyclic adenosine 3',5'-monophosphate (cyclic 3',5'-AMP) produced an inhibition resembling that produced by a beta-adrenoceptor agonist.5. In critical concentrations theophylline augmented and imidazole inhibited beta-adrenoceptor mediated responses, as well as responses to dibutyryl cyclic AMP. However, additional actions of theophylline and imidazole were also demonstrated.6. Responses mediated by alpha-adrenoceptors, but not those mediated by beta-adrenoceptors, were blocked by membrane stabilizers, quinidine being the most potent of those studied.7. The results are discussed in relation to the possible mechanisms of action of alpha- and beta-adrenoceptor agonists.     

Distribution of α- and β-adrenoceptors in human urinary bladder

1 The distribution of alpha- and beta-adrenoceptors in isolated preparations of human bladder neck and detrusor muscle has been studied.2 Adrenaline caused contraction of the bladder neck which was blocked by phenoxybenzamine but unaltered by propranolol.3 Isoprenaline caused relaxation of the bladder neck which was blocked by propranolol. High concentrations caused contraction which was enhanced by propranolol but blocked by phenoxybenzamine.4 Detrusor muscle was relaxed by isoprenaline and this effect was blocked by propranolol. Phenylephrine caused relaxation of detrusor which was unaffected by phenoxybenzamine; in some cases contraction was produced in the presence of propranolol.5 It is concluded that the bladder neck contains mainly alpha-receptors and the detrusor mainly beta-receptors but both regions posses both types of adrenoceptor.     

The structure-activity relationships of the antiviral chemotherapeutic activity of isatin β-thiosemicarbazone

As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure-activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin β-thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin β-thiosemicarbazone as a standard. The overall dimensions of the isatin β-thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as all substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the -CS.NH₂ group in relation to the ring nitrogen was found to be critical, as the α-thiosemicarbazone was inactive. A number of modifications of the side-chain were investigated:all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1-ethylisatin β-thiosemicarbazone, with an activity of 286 (isatin β-thiosemicarbazone100). Isatin β-thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed on activity against ectromelia.     

Protective Effects of the Hydroethanolic Extract of Fridericia chica on Undifferentiated Human Neuroblastoma Cells Exposed to α-Zearalenol (α-ZEL) and β-Zearalenol (β-ZEL)

Fridericia chica (Bignoniaceae) is a traditional medicinal plant. The aim of this research was to determine the protective effects of the hydroethanolic extract from the F. chica leaves (HEFc) against the cytotoxicity of zearalenone (α-ZEL) and β-ZEL on SH-SY5Y cells. Free radical scavenging activity of HEFc was evaluated using the DPPH method. The cytotoxicity of both zearalenone metabolites and HEFc was examined using MTT test, as was the cytoprotective effects of the HEFc on cells treated with these mycotoxins. The chemical composition of HEFc was determined using UPLC-QTOF-MS/MS. HEFc elicited good DPPH radical scavenging activity following a concentration-dependent relationship. Cells exposed to α-ZEL exhibited a viability ˂50% after 48 h of treatment (25 and 50 µM), while those exposed to β-ZEL showed viability ˂50% (100 µM) and ˂25% (25-100 µM) after 24 and 48 h of exposure, respectively. HEFc showed a significant increase in cell viability after exposure to α-ZEL (25 and 50 µM) and β-ZEL (6–100 µM) (p < 0.05). UPLC-QTOF-MS/MS analyses allowed the identification of 10 phytochemical components in the HEFc. In short, the hydroethanolic extract of F. chica grown in Colombian Caribbean can protect against the effects of mycotoxins and it is a valuable source of compounds with antioxidant properties.     

Release of β-lipotropin- and β-endorphin-like material induced by angiotensin in the conscious rat

1 Groups of mice were pretreated with the 5-hydroxytryptamine (5-HT) depletors, fenfluramine or p-chlorophenylalanine (PCPA), followed by pethidine or morphine. 2 Fenfluramine alone produced a short lasting analgesia but PCPA was without any effect. 3 Pethidine and morphine both increased hot plate reaction times measured after 30 min. 4 Pretreatment with PCPA attenuated morphine analgesia but did not affect pethidine analgesia. Fenfluramine did not alter the response to either analgesic. 5 PCPA produced a significant depletion of brain 5-HT levels which was not reversed by the analgesics. The fenfluramine-induced decrease in 5-HT was reversed by morphine but not by pethidine. 6 The results support the involvement of 5-HT in the antinociceptive action of morphine in the mouse.     

Temperature modulation of α- and β-adrenoceptors in the isolated frog heart

1. The effects of adrenaline on the isolated frog's heart at 27 degrees C are not antagonized by phentolamine (1.5 x 10(-6)M) but are abolished at 7 degrees C.2. At 27 degrees C isoprenaline was more potent than noradrenaline, but at 7 degrees C noradrenaline was more potent than isoprenaline.3. Phenoxybenzamine (1.5 x 10(-5)M) or dibenamine (1.5 x 10(-5)M) at 7 degrees C abolished the work output induced by adrenaline. When the temperature was raised to 24 degrees C, adrenaline caused an increase in work output.4. It is concluded that in the isolated frog heart there are at least two pools of adrenoceptors, the availability of which can be governed by temperature.     

BRL 46470A: a highly potent,selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties

The novel 5-HT₃ antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT₃ receptor antagonism, BRL 46470A was shown to antagonise 5-HT₃ mediated responses in the guinea-pig ileum [pA₂ 8.3±0.5, slope 0.98±0.20, mean±SEM (5)], the rabbit isolated heart (pA₂ 10.1±0.1, slope 1.2±0.2,n=5) and the rat Bezold-Jarisch model (ID₅₀ 0.7 µg/kg IV±0.1,n=8), with a long duration of action (>3 h). BRL 46470A selectively displaced [³H]-BRL 43694 from 5-HT₃ binding sites in rat brain membranes (K_i 0.32 nM±0.04,n=4) without displacing (at concentrations greater than 1 µM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects-elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001–0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT₃ receptor antagonist ondansetron, with no evidence of a bell-shaped dose response curve over 4 orders of magnitude. BRL 46470A (0.0001 and 0.01 mg/kg SC) also reduced the anxiogenic effects of m-CPP (1-(3-chlorophenyl) piperazine) in the rat elevated X-maze. BRL 46470A is therefore a chemically novel potent and selective 5-HT₃ receptor antagonist with anxiolytic potential and a long duration of action in animal studies.