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PubMed1983

Metabolism of imipramine in vitro: synthesis and characterization of N-hydroxydesmethylimipramine.

The synthesis of N-hydroxydesmethylimipramine via the corresponding primary hydroxylamine and oxime is described. The N-oxygenated products are unstable to g.l.c. analysis without prior derivatization; the decomposition products are identified by g.l.c.-mass spectrometry. N-Hydroxydesmethylimipramine is shown to be a metabolite of imipramine and desmethylimipramine on incubation of either with fortified 9000 g liver homogenates of male New Zealand white rabbits. The metabolic product is characterized by mass spectrometry and n.m.r. Didesmethylimipramine is shown to undergo metabolic alpha-C-oxidation, to yield the carboxylic acid, 3-(10,11-dihydro-5H-dibenz[b, f]azepin-5-yl)propionic acid, but not N-oxidation. N-Hydroxydesmethylimipramine is metabolically reduced to desmethylimipramine and metabolized further to 10-hydroxydesmethylimipramine, 2-hydroxydesmethylimipramine and the carboxylic acid. The possible role of N-hydroxydesmethylimipramine and 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propionic acid in the formation of iminodibenzyl is discussed.

Animals↗
PubMed1989

[Microbial mutagenicity testing of N-nitrosoiminostilbene and N-nitrosoiminodibenzyl, the nitrosation products of the drugs carbamazepine and trimipramine hydrochloride].

The active agents of the drugs Finlepsin and Herphonal, carbamazepine and trimipramine, were nitrosated under simulated human gastric conditions. For both formed N-nitroso compounds, N-nitroso iminostilbene (N-nitroso-5H-dibenz(b,f)azepine) and N-nitroso iminodibenzyl (N-nitroso-10,11-dihydro-5H-dibenz(b,f)azepine), tests for mutagenic potency in the Ames-test gave negative results.

Carbamazepine↗
PubMedDate not supplied

The metabolism of mianserin in women, rabbits, and rats: identification of the major urinary metabolites.

The biotransformation of orally administered 3H-mianserin was investigated in female human subjects, rabbits, and rats by identification of the major urinary metabolites. Three days after dosing, the urinary excretion of radioactivity was 53% in women, 36% in rats, and 80% in rabbits. In the women's urine, 15% of the administered dose was excreted in the form of mianserin (conjugated plus nonconjugated); in the animal species this quantity was 1-2%. Mianserin was predominantly metabolized to 8-hydroxy analogs in all species; in rats, 8-hydroxydesmethylmianserin was the principal metabolite. Demethylation was an important metabolic pathway in the animal species, but not in women. Novel N-formyl compounds were detected in the urine of both animal species, but the possibility that these were artifacts formed during extraction with chloroform cannot be ruled out. Trace amounts of two compounds in which the piperazine moiety of mianserin was absent, 11H-dibenz[b,e]azepine and 11 H-dibenz[b,e]azepine-2-ol, were identified in the urine of rabbits and rats, respectively.

Adult↗
PubMed1993

Dopamine D1 receptor involvement in the discriminative-stimulus effects of SKF 81297 in squirrel monkeys.

The discriminative-stimulus effects of the selective dopamine D1 agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 81297) were investigated in squirrel monkeys trained to discriminate i.v. injections of SKF 81297 from saline in a two-lever drug-discrimination procedure. SKF 81297 produced dose-related increases in responding on the SKF 81297-associated lever with full substitution occurring at the training dose in all monkeys. Pretreatment with the selective D1 antagonist(-)-trans-6-7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N- methyl-5H- benzo(d)naphtho-(2,1-b)azepine 2-(SCH 39166) and the D1 partial agonist 7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 75670) produced rightward shifts of the dose-effect curve for the discriminative-stimulus effects of SKF 81297, indicative of surmountable antagonism. Pretreatment with the selective D2 antagonist eticlopride, however, did not systematically alter the discriminative-stimulus effects of SKF 81297. Stereoselectivity was evident in the discriminative-stimulus effects of the enantiomers of the structurally related D1 agonist 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benz azepin e (6-Br-APB), with the R-, but not the S-enantiomer, producing dose-related increases in responding on the SKF 81297-associated lever and full substitution in all monkeys. Another selective D1 agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine (SKF 82958) and the nonselective D1/D2 agonists (-)apomorphine and (-)4,6,6a,7,8,12b-hexahydro-7 methyl-indolo[4,3-ab]phenanthridine (CY 208-243), also engendered dose-related increases in SKF 81297-appropriate responding with full substitution occurring in one-half of the monkeys studied. The D2 agonists, (+)-4-propyl-9-hydroxynaphthoxazine and quinpirole, engendered dose-related increases in SKF 81297-appropriate responding but did not substitute fully in any monkey studied. Other dopaminergic drugs, including the D1 partial agonists SKF 75670 and R(+)-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3- benzazepine (R-SKF 38393), and the indirect dopamine agonists, cocaine, d-amphetamine and 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909), did not substitute fully for SKF 81297 in any monkey studied. These results suggest that agonist actions at the D1 subtype of dopamine receptor are prominently involved in the discriminative-stimulus effects of SKF 81297.

Animals↗
PubMed1977

[Stability of the amidine analogs of penicillin and deacetoxycephalosporin to the penicillinase of Bacillus licheniformis 749/c].

Fermentative hydrolysis of 3 derivatives of 6-beta-amidinopenicillanic acid and I derivative of 7-beta-amidinodeacetoxycephalosporanic acid by penicillinase produced by Bacillus licheniformis 749/c was studied. It was found that 6-beta-[(hexahydro-IH-azepin-I-yl) methyleneamino] penicillanic acid, 6-beta-(N1 N-dimethylformamidino-N1) penicillanic acid and 6-beta [(morpholin-I-yl) methylenemino] penicillanic acid were hydrolyzed by the enzyme 50, 70, and 160 times respectively slower than benzylpenicillin. 7-beta-[(Hexahydro-IH-azepin-I-yl)' methylenemino] deacetoxycephalosporanic acid proved to be at least 10 times more stable to the effect of penicillinase than methicillin. In addition unlike the amidine analogues of penicillin the above compound had an inhibitory effect on penicillinase produced by Bacillus licheniformis 749/c.

Amidines↗
PubMed2002

Octakis-6-sulfato-gamma-cyclodextrin as additive for capillary electrokinetic chromatography of dibenzoazepines: carbamazepine, oxcarbamazepine and their metabolites.

Single isomer octakis-(2,3-dihydroxy-)6-sulfato-gamma-cyclodextrin used as pseudostationary phase of the background electrolyte interacts with dibenzo[b,f]azepines (consisting of a condensed 3-ring system) and forms negatively charged complexes. Hydroxygroups in position 2 and 3 at carbamazepine increase the extent of interaction, whereas substitution by oxygen at position 10 and/or 11 reduces it. The complex constants for the analytes are ranging from few tens L/mol (10-hydroxycarbamazepine, 10,11-dihydroxycarbamazepine, 10,11-epoxycarbamazepine, oxcarbazepine) to several hundreds L/mol (carbamazepine, 2-hydroxycarbamazepine, 3-hydroxycarbamazepine), and are much larger than those of the analytes with octakis-(2,3-dimethyl-)-6-sulfato-gamma-cyclodextrin. Full enantiomeric separation of the chiral metabolites of carbamazepine and oxcarbazepine is obtained at octakis-(2,3-dihydroxy-)-6-sulfato-gamma-cyclodextrin concentrations of about 10 mM (3 mM borate buffer, pH 8.5). Compared to heptakis-6-sulfato-beta-cyclodextrin, selectivity differs and stereoselectivity is more pronounced.

Azepines↗
PubMed1989

Meptazinol and morphine in postoperative pain assessed with a new method for onset and duration.

Meptazinol, m-(3-ethyl-1-methyl-hexahydro-1-H-azepin-3-yl) phenol hydrochloride is a centrally active opioid analgesic with a specificity for the mu-1 receptor. It has been reported to lack many of the side effects commonly observed with morphine and morphinelike drugs in man. The objective of this study was to assess the analgesic efficacy and safety of meptazinol (50 mg and 100 mg) relative to morphine (5 mg and 10 mg) when administered intramuscularly for the treatment of postoperative pain. In addition, a new clinical method for measuring onset and duration and a statistical technique for evaluating the study data are presented. One hundred and seventeen patients were evaluated for 6 hours in a randomized double blind, single dose, parallel-groups trial. Estimates of relative potency for hourly pain and relief parameters, and the summary variables sum of pain intensity differences (SPID) and total pain relief (TOTPAR) were performed. The estimate of relative potency of meptazinol to morphine for pain relief was 0.19 at 1/2 hour (i.e. 100 mg of meptazinol was approximately equivalent to 20 mg of morphine). Thereafter, there was a rapid decline of efficacy for meptazinol, with a relative potency estimate of 0.12 at 1 hour and 0.06 at 2 hours. The distribution functions for several time related events were estimated including time to onset, duration and time to remedication. The two drugs had approximately equal onset, but meptazinol had significantly shorter duration. More patients on meptazinol required remedication with a rescue analgesic and at an earlier time than patients on morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Transdermal delivery of drugs with differing lipophilicities using azone analogs as dermal penetration enhancers.

Six model drugs were selected for this study based on their degree of lipophilicity as represented by their log P values (range = -0.95 to 3.51). They included 2,4-dihydroxy-5-fluoropyrimidine (5-fluorouracil); 1,3,7-trimethylxanthine (caffeine); [(2-hydroxybenzoyl)amino]-acetic acid (salicyluric acid); 2-hydroxybenzoic acid (salicylic acid); 9 alpha-fluoro-16 alpha-hydroxyprednisolone 16 alpha, 17 alpha-acetonide (triamcinolone acetonide); and alpha-methyl-4-[2-methylpropyl]benzeneacetic acid (ibuprofen). Six dermal penetration enhancers [Azone or 1-dodecylhexahydro-2H-azepin-2-one (1), N-dodecyl-2-pyrrolidinone (2), N-dodecyl-2-piperidinone (3), N-dodecyl-N-(2-methoxyethyl)acetamide (4), N-(2,2-dihydroxyethyl)dodecylamine (5), and 2-(1-nonyl)-1,3-dioxolane (6)] were tested in vitro across full-thickness hairless mouse skin with each of the drugs. The relationship between lipophilicity (log P) and efficacy (represented by the enhancement ratio of flux) of the drugs when coadministered with the enhancers was examined using linear regression. The three cyclic enhancers (1-3) exhibited linear relationships, indicating that they were more effective at enhancing the penetration of hydrophilic drugs R2 = 0.8997 for 1, 0.8801 for 2, and 0.804 for 3) when evaluating all the model drugs except triamcinolone acetonide (TA). The two acyclic enhancers (4 and 5) showed a similar relationship, but their correlation coefficients were lower at 0.6463 for 4 and 0.6213 for 5. Studies with the dioxolane (6) yielded no relationship between the lipophilicity of the drug and the efficacy of the enhancer, with an R2 of 0.002. Overall, 6 was the least effective enhancer studied. The steroid TA was not included in the linear regression analysis. Of the six model drugs studied, TA exhibited the largest increase in transdermal delivery when enhancers 1-6 were used.

Animals↗
PubMed2006

Quantification of serotonin 5-HT1A receptors in monkey brain with [11C](R)-(-)-RWAY.

[11C](R)-(-)-RWAY ([11C]2, 3, 4, 5, 6, 7-hexahydro-1{4-[1[4-(2-methoxyphenyl)-piperazinyl]]-2-phenylbutyry}-1H-azepine) is a new radioligand for imaging brain 5-HT1A receptors with positron emission tomography. In [11C](R)-(-)-RWAY, the direction of the amide bond is expected to reduce metabolism by hydrolysis while allowing easy 11C-labeling at the methoxy position. The purposes of this study were to evaluate different tracer kinetic models in nonhuman primates to quantify 5-HT1A receptors with [11C](R)-(-)-RWAY and to test for the possible action of P-glycoprotein (P-gp), one of the known efflux pumps at the blood-brain barrier. The brain uptake of radioactivity from [11C](R)-(-)-RWAY into 5-HT1A receptor-rich brain regions was severalfold greater than for its antipode ([11C](S)-(+)-RWAY) and could be displaced by receptor saturating doses of the selective 5-HT1A antagonist, WAY-100635. Pretreatment with tariquidar, a potent inhibitor of P-gp, increased brain uptake of [11C](R)-(-)-RWAY about 1.5-fold and the plasma free fraction about 1.8-fold. Thus, the effect of tariquidar on brain uptake may have been caused by displacement of the radioligand binding to plasma proteins. Mathematical modeling showed that the estimated values of regional binding potential were correlated strongly between two-tissue compartment model and multilinear reference tissue model, and thus, supported the use of the cerebellum as a reference region.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Environmental fate of rice pesticides in California.

Each of the pesticides reviewed is reported to dissipate from field water after application. Carbofuran is hydrolyzed rapidly under the alkaline conditions usually found in the rice field environment, and its hydrolysis products are also degraded rapidly. The longest half-life reported (18-26 d) was in water that overlaid soil treated with Furadan granular formulation. Generally, carbofuran dissipation ranged from 36 hr to 3 d. Under field application, bensulfuron methyl showed a half-life of 1-3 d, but others have recovered all of the "dissipated" herbicide in the soil compartment. MCPA applied to rice fields is reportedly degraded by the joint action of sunlight and microbial action with a half-life of 3-5 d. Methyl parathion showed a maximum half-life of 9-17 d in a model aquatic ecosystem, but other reports found more rapid dissipation. The half-life of molinate has been observed by numerous researchers to be less than 5 d, with volatility the major route of loss. A half-life as short as 5-7 d has been reported for thiobencarb applied to rice fields, but others report much longer periods; volatility again is expected to be a significant route of loss. Microbial degradation takes place with each of the subject pesticides. Numerous authors have reported enhanced degradation of carbofuran under conditions of repeated application, and this probably holds true for the others. A specialized segment of the microbial population (Pseudomonas spp.) is purported to carry out most of the degradation but is inefficient at degrading the hydrolysis product, carbofuran phenol. Biodegradation of bensulfuron methyl has been observed with actinomycetes, fungi, and bacteria, and takes place primarily by oxidation and hydrolysis. Methyl parathion is biodegraded primarily by nitro reduction to aminomethyl parathion. A fungus, an actinomycete, and a bacterium were shown to biodegrade molinate, primarily by oxidation at the sulfur atom and the azepine ring. Thiobencarb is biodegraded in anaerobic sediments at a slow rate; the dechlorinated thiobencarb was shown to cause dwarfing of rice in some fields. Otherwise, its aerobic biodegradation is rapid and follows the same routes as with molinate. Carbofuran is a systemic insecticide that is rapidly absorbed and translocated to aerial parts of the plant. Carbofuran is metabolized in rice plants to the corresponding phenol, which is irreversibly bound into the plant, as well as to 3-hydroxycarbofuran and other minor components; it is depurated through leaf exudate, from which it volatilizes. Rice plants were observed to take up more bensulfuron methyl through shoots than roots and to metabolize it to the 4-hydroxy analog. The half-life of methyl parathion in Hydrilla verticulla, an aquatic macrophyte, was 1 wk, but little has been reported on methyl parathion in plants. Barnyardgrass was found to absorb greater amounts of molinate than did rice, and it produced larger proportions of basic metabolites, which may form the basis for its selective toxicity. Thiobencarb has been shown to be rapidly absorbed, translocated, and metabolized in rice plants, barnyardgrass, and the broadleaved wild amaranth, smartweed, and lambsquarters. Translocation was more rapid and extensive in barnyardgrass than in rice, and most of the 14C radiolabel was recovered as metabolites. Its terminal metabolite, chlorobenzoic acid, was taken up into lignin-like plant constituents. It is apparent that information on plant uptake and biodegradation is limited--none exists for woody species--but the fact that some species appear resistant to the herbicides suggests that biodegradative ability is general. (ABSTRACT TRUNCATED)

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1987

B-HT 920 and B-HT 958: presynaptic effects on electrically evoked 3H-dopamine release from slices of rat nucleus accumbens.

The effects of two thiazoloazepine derivatives, B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine) and B-HT 958 (2-amino-6-(p-chloro-benzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]a zepine) on electrically evoked overflow of 3H-dopamine were studied. Slices from nucleus accumbens of the rat were preincubated with 3H-dopamine and superfused at 23 degrees C or 37 degrees C. Electrical field stimulation was applied using frequencies of 0.5 or 5 Hz. At 37 degrees C/5 Hz, B-HT 920 markedly and dose-dependently (0.01-0.1 mumol/l) reduced the stimulation evoked overflow of tritium. Its dose-response curve was shifted to the right at 23 degrees C/0.5 Hz and 23 degrees C/5 Hz, respectively. A similar result was obtained with the dopamine receptor agonist, apomorphine (1 mumol/l). B-HT 958 (0.1-10 mumol/l) also reduced electrically induced overflow of tritium at 37 degrees C/5 Hz, had no effect at 23 degrees C/0.5 Hz, and facilitated tritium overflow at 23 degrees C/5 Hz. Sulpiride (10 mumol/l) completely prevented the effects of B-HT 920 (1 mumol/l) or B-HT 958 (1 mumol/l) at 37 degrees C/5 Hz, whereas phentolamine (1 mumol/l) had no effect on the actions of the two drugs under these experimental conditions. From the patterns of effects obtained under the different experimental conditions it is concluded that B-HT 920 acts as full agonist at presynaptic dopamine autoreceptors whereas B-HT 958 acts as partial agonist.

Adrenergic alpha-Agonists↗
PubMed1989

The inhibition of alpha 1-adrenoceptor-mediated contractions of rabbit pulmonary artery by Ca2+-withdrawal, pertussis toxin and N-ethylmaleimide is dependent on agonist intrinsic efficacy.

Contractions were induced in rings of rabbit pulmonary artery with the preferential alpha 1-adrenoceptor agonists, phenylephrine, methoxamine and St 587 [2-(2-chloro-trifluoromethyl-phenylimino)imidazolidine and the preferential alpha 2-adrenoceptor agonists, clonidine and B-HT 920 [6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine] [corrected]. Phenylephrine and methoxamine acted as full agonists whereas St 587, clonidine and B-HT 920 were partial agonists (intrinsic activities 0.62, 0.38 and 0.42, respectively). Experiments with alpha 1- and alpha 2-adrenoceptor antagonists indicated that the receptors involved are of the alpha 1 type only. Removal of extracellular Ca2+ inhibited maximal contractions to phenylephrine and methoxamine by 30% and 49%, respectively. The remaining contraction components of the full agonists were abolished by the "intracellular Ca2+ antagonist" TMB-8 [8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate]. Contractions to St 587, clonidine and B-HT 920 were virtually abolished in Ca2+-free medium. Pretreatment of the donor rabbits with pertussis toxin (2.5 micrograms/kg i.v., 5-6 days before sacrifice) attenuated the efficacies of the full agonists, phenylephrine and methoxamine by only 24% and 17%, respectively, whereas maximal contractions to the partial agonists, St 587, clonidine and B-HT 920, were inhibited by 46%, 61% and 75%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1989

Occurrence of yawning and decrease of prolactin levels via stimulation of dopamine D2-receptors after administration of SND 919 in rats.

SND 919 [S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole) is expected to have a potent and selective dopamine D2-receptor agonistic activity. From this information, the present study was performed to investigate effects of SND 919 on yawning behavior and prolactin secretion in rats. Subcutaneous injections of SND 919 (25-500 micrograms/kg, s.c.) elicited yawning responses. Its dose-response curve was bell-shaped with maximal effects at a dose of 100 micrograms/kg. Yawning behavior was also evoked by the putative dopamine autoreceptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]azepine) (B-HT 920) (5-100 micrograms/kg, s.c.) and (+)-3-PPP ((+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine) (5-15 mg/kg, s.c.). The yawning induced by SND 919 (100 micrograms/kg, s.c.) as well as talipexole (25 micrograms/kg, s.c.) was inhibited by pretreatment with dopamine D2-receptor antagonists such as spiperone (0.5 mg/kg, i.p.) and YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-met hylamino- benzamide) (0.1 mg/kg, i.p.), or the muscarinic receptor antagonist, scopolamine (0.5 mg/kg, i.p.). However, the yawning was not affected by the dopamine D1-receptor antagonist, SCH 23390 (R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-o l) (0.5 mg/kg, i.p.). Stereotypy such as licking and biting was not observed following the administration of SND 919, talipexole and (+)-3-PPP. Administration of SND 919, talipexole or (+)-3-PPP in respective yawn-inducing doses caused a reduction in both the basal prolactin levels and the alpha-methyl-p-tyrosine-induced hyperprolactinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Subtype determination of presynaptic alpha 2-autoreceptors in the rabbit pulmonary artery and human saphenous vein.

The pharmacological properties of the presynaptic a2-autoreceptors mediating inhibition of noradrenaline release were investigated in human saphenous vein and rabbit pulmonary artery. Segments of these blood vessels were incubated with [3H]noradrenaline and subsequently superfused with physiological salt solution containing uptake1 and uptake2 blockers. The potencies of a2-adrenoceptor antagonists in facilitating (pEC40) the electrically (2 Hz) evoked tritium overflow were determined. The order of potency and potency ratios of a2-adrenoceptor antagonists obtained in our experiments were compared with the corresponding order of affinity and affinity ratios from radioligand binding studies in tissues and cells expressing only one of the alpha 2-adrenoceptor subtypes. In the rabbit pulmonary artery, oxymetazoline was a highly potent agonist at presynaptic a2-adrenoceptors, as reflected by its ability to inhibit at low concentrations the electrically evoked tritium overflow. However, in the human saphenous vein oxymetazoline behaved as a partial agonist, which, in interaction experiments with the a2-adrenoceptor agonist B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine), exhibited high potency in antagonizing the inhibitory effect of the latter drug on tritium overflow. Prazosin given alone at concentrations up to 1 mumol/l did not affect tritium overflow. The data obtained with oxymetazoline and prazosin make it very improbable that the a2-autoreceptors on the sympathetic nerves in both tissues are of the a2B- or a2C-subtype. In both blood vessels, rauwolscine given alone was highly potent in facilitating the electrically evoked overflow. In agreement with this, rauwolscine exhibited high potency in antagonizing the inhibitory effect of oxymetazoline on tritium overflow in the rabbit pulmonary artery and of B-HT 920 in the human saphenous vein. The ratio phentolamine/rauwolscine calculated from their potencies in increasing the electrically evoked tritium overflow was also used to discriminate between the various a2-adrenoceptor subtypes. Comparison of this potency ratio with the corresponding affinity ratios for a2-adrenergic binding sites on HT 29 cells, human platelets, bovine pineal gland, rat submaxillary gland, and cell lines transfected with the human a2 genes indicates that in the rabbit pulmonary artery and human saphenous vein the pharmacological characteristics of the autoreceptors conform best to those of a2A-adrenoceptors. Finally, in both blood vessels the potencies of the antagonists BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), rauwolscine, corynanthine, phentolamine, idazoxan, SKF 104078 (6-chloro-9-[(3-methyl-2-butenyl) oxyl]-3-methyl-1H-2,3,4,5-tetrahydro-3-benzazepine), and/or tolazoline in facilitating evoked noradrenaline release was determined. The potencies of these drugs which can discriminate between a2A- and a2D-adrenoceptors (but not between these and a2B/2C-adrenoceptors) were correlated significantly with their affinities for a2A, but not a2D, sites in radioligand binding studies. In conclusion, the present results suggest that the sympathetic nerves of the human saphenous vein and rabbit pulmonary artery are endowed with a2-autoreceptors of the a2A subtype.

Adrenergic alpha-Agonists↗
PubMed1981

Modulation of motor activity by alpha 1- and alpha 2-adrenoceptor stimulation in mice.

The influence of two alpha-adrenoceptor agonists, clonidine and B-HT 920, on motor activity was tested in mice. Both, clonidine and B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine) in the dose range 30--300 micrograms/kg s.c. effectively inhibited exploratory activity. On the other hand only clonidine, which stimulates alpha 2- and alpha 1-adrenoceptors increased locomotor activity in mice treated with reserpine (5 mg/kg) and apomorphine (3 mg/kg) in the doses of 0.3 and 1 mg/kg i.p. The highly selective alpha 2-agonist B-HT 920 was ineffective under these conditions up to 30 mg/kg i.p. It is concluded, that in mice "sedative" alpha-adrenoceptors are of the alpha 2- and "excitatory" of the alpha 1-type.

Adrenergic alpha-Agonists↗
PubMed1980

Vasoconstriction mediated by postsynaptic alpha 2-adrenoceptor stimulation.

The postsynaptic alpha-adrenoceptors involved in vasoconstriction brought about by B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin) administered i.v. to pithed, normotensive rats were characterized. The rate of onset of the hypertensive response to i.v. B-HT 933 is slower than that induced by (-)-phenylephrine, an agonist of alpha 1-adrenoceptors. The antagonism of the alpha-adrenoceptor blocking drugs rauwolscine, yohimbine and corynanthine was quantified towards B-HT 933-induced increases in diastolic pressure. Rauwolscine (pA2 = 7.06) and yohimbine (pA2 = 6.83) were effective antagonists, whereas corynanthine proved much less potent (pA2 = 5.03). On the basis of the reported selectivity of yohimbine and its two diastereoisomers rauwolscine and corynanthine for alpha 1- and alpha 2-adrenoceptors, it is concluded that the postsynaptic alpha-adrenoceptors triggered by B-HT 933 are of the alpha 2-type. B-HT 933 identifies a subclass of postsynaptic alpha 2-adrenoceptors in vascular smooth muscle distinct from postsynaptic alpha 1-adrenoceptors. Both types of alpha-adrenoceptors are likely to be involved in the mediation of vasoconstriction.

Animals↗
PubMed1982

B-HT 958, a new alpha-adrenoceptor agonist with a high pre/postsynaptic activity ratio.

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo [5,4-d] azepine) was a potent agonist at presynaptic and a less potent agonist at postsynaptic alpha-adrenoceptor sites. Presynaptically this was shown in pithed rats by the inhibition of tachycardia evoked by sympathetic nerve stimulation (0.2 Hz). The 50% inhibitory dose (ID50) was 0.3 mg/kg i.v. Moreover in isolated perfused cat hearts, the drug inhibited the tachycardia and the outflow of noradrenaline induced by sympathetic nerve impulses. These effects of B-HT 958 were antagonized by phentolamine or yohimbine. At postsynaptic sites high doses of B-HT 958 increased the blood pressure of decentralized rats. The dose which increased pressure by 30 mm Hg (PD 30) was 46.3 mg/kg i.v. This effect was antagonized by rauwolscine 5 mg/kg i.v. After pretreatment with reserpine (7.5 mg/kg i.p., 18 h) B-HT 958 proved much more potent (PD 30 = 0.6 mg/kg i.v.) and its effect was strongly antagonized by yohimbine but hardly by prazosin. The dose of yohimbine which shifted the dose-response curve of B-HT 958 by the factor of 10 (D10) to the right was 1.8 mg/kg iv., the corresponding dose of prazosin was 1,900 mg/kg i.v. (extrapolated). B-HT 958 showed also alpha-adrenoceptor blocking properties. This was demonstrated presynaptically in pithed rats by the drug-induced augmentation of tachycardia elicited by electrical stimulation at high frequency (6.4 Hz). At postsynaptic sites B-HT 958 antagonized the blood pressure increase-caused by B-HT 920 (alpha 2; D10 = 1.1 mg/kg i.v.) but not that caused by methoxamine (alpha1). It is concluded that B-HT 958 is a partial agonist at peripheral alpha 2-adrenoceptors. In doses of about 1 mg/kg and with low frequency sympathetic stimulation (less than 6.4 Hz) it acts presynaptically as agonist; in this dose the drug acts postsynaptically mainly as antagonist.

Adrenergic alpha-Agonists↗