SEARCH · PubMed Health

Results for “Azabicyclo Compounds”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 1,063 records · Page 59Linked to original sources

PubMed1992

Nonadrenergic, noncholinergic contractile responses of the guinea pig hilar bronchus involve the preferential activation of tachykinin neurokinin2 receptors.

Experiments were designed to characterize receptor(s) that mediate nonadrenergic, noncholinergic contractions of the guinea pig hilar bronchus using selective neurokinin (NK)1 (CP 96,345) and NK2 (R396 and MEN 10,376) tachykinin receptor antagonists. Left and right hilar bronchi were studied as pairs in the presence of atropine, propranolol, phentolamine; indomethacin and thiorphan. (2S, 3S)-cis-2-(diphenylmethyl)-N-(2-methoxyphe nyl)-1-azabicyclo[2,2,2]octan-3-amine (CP 96,345) selectively antagonized contractions of the bronchus to the NK1 agonist Ac-[Arg6,Sar9,Met(O2)11]-SP(6-11) with a -log molar KB value of about 8.0. Similarly, Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R396) and [Tyr5, D-Trp6,8,9, Lys10]-NKA(4-10) (MEN 10,376) selectively antagonized contractions to the NK2 agonist [beta Ala8]-NKA(4-10) with -log molar KB values of about 5.5 and 6.7, respectively. CP 96,345 (3 x 10(-7) M) had no effect on contractions evoked by transmural electrical stimulation (TES). However, both R396 (1 x 10(-5) to 1 x 10(-4) M) and MEN 10,376 (1 x 10(-6) to 1 x 10(-5) M) caused blockade of responses to TES. CP 96,345 (3 x 10(-7) M) antagonized TES-induced contractions only when studied after substantial blockade by R396 or MEN 10,376. Contractions to TES were not abolished by R396, MEN 10,376 or a combination of these antagonists with CP 96,345. R396 (1 x 10(-6) M) increased the maximum contraction to TES and potentiated the frequency-response curve in bronchi treated with MEN 10,376 (1 x 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Gastroprokinetic properties of the benzimidazolone derivative BIMU 1, an agonist at 5-hydroxytryptamine4 and antagonist at 5-hydroxytryptamine3 receptors.

We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride) and its binding profile at 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors, in an attempt to assess the serotonergic mechanism underlying its prokinetic action. BIMU 1 dose-dependently (0.01-0.3 mg/kg i.v.) increased the motility of a denervated pouch of canine stomach. This excitatory action was sensitive to muscarinic blockade. A similar stimulatory effect was exerted by the benzamidic prokinetic agent cisapride (0.03-0.3 mg/kg i.v.) but not by the 5-HT3 receptor antagonist ondansetron (up to 1 mg/kg i.v.). The significance for propulsive efficacy of the motor stimulating activity of BIMU 1 was evaluated in a model of gastric emptying of liquids in the conscious dog. The emptying rate of a non-caloric liquid meal instilled through a gastric fistula was accelerated by both BIMU 1 (0.01-1 mg/kg i.v. and 0.1-3 mg/kg p.o.) and cisapride (0.03-1 mg/kg i.v. and 0.3-10 mg/kg p.o.). Ondansetron (1 mg/kg i.v.) did not show any effect. The activity of the 5-HT4 receptor antagonist DAU 6285 was evaluated in the gastric emptying model per se and in interaction experiments on the accelerating action of BIMU 1 (0.3 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Humoral and blood pressure effects of the angiotensin converting enzyme inhibitor ramipril in essential hypertension.

The humoral and antihypertensive activities of the angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3.3.0] octane-3-carboxylic acid (ramipril, Hoe 498) were investigated in 10 patients with essential hypertension (WHO stage I or II). After a 7-day placebo period, the patients were treated with 5 mg ramipril orally once daily for 14 days. Peak serum concentrations of the active metabolite M1 (dicarboxylic acid) of 5.4-62.0 ng/ml were observed 2-6 h after the first oral dose. The maximum ACE inhibition of 95% was reached 2-4 h after the first oral dose, inhibition exceeded 70% 24 h after dosing. The maximum drop in the systolic and diastolic blood pressure (random zero sphygmomanometer) was measured 4 h after ramipril (p less than 0.02, p less than 0.01), but blood pressure on days 7 and 14 of the treatment period was not different from pretreatment values. Automatically recorded blood pressure results showed a marked reduction of both systolic and diastolic blood pressure during treatment compared to placebo. No side effects occurred. From the present data it is concluded that ramipril is a potent ACE inhibitor in hypertensive patients and that further controlled studies are required for the evaluation of the antihypertensive effect of 5 mg ramipril in essential hypertension.

Adult↗

PubMed1998

Characterization of the neurochemical effects of N-[2-(1-azabicyclo[3,3,0]octan-5-yl)ethyl]2-nitroaniline fumarate (SK-946) as a cognition activator.

The neurochemical effects of SK-946, N-[2-(1-azabicyclo[3,3,0]octan-5-yl)ethyl]2-nitroaniline fumarate, were investigated in an attempt to elucidate cognition activating properties. In rat brain cortical membranes and in cloned human receptors expressed in Sf9 cells, SK-946 had submicromolar affinities for muscarinic receptors with a moderate selectivity for M1 (m1) sites. Although no increase in the antagonist (N-methylscopolamine)/agonist (oxotremorine-M) binding ratio was observed, SK-946 exhibited a partial agonistic effect on receptor-stimulated phosphoinositide hydrolysis in primary cultured rat fetal hippocampal cells. Heterogeneous, reversible and concentration-dependent excitations of the hippocampal neuronal cells treated with SK-946 (10(-5)-10(-3) M) were confirmed as increases in cytosolic Ca2+ concentrations measured in Fura-PE3 preloaded cells. Furthermore, SK-946 (>10(-5) M) increased [3H]myo-inositol uptake into the hippocampal cells. On the other hand, SK-946 had no effect on adenylate cyclase activities in primary cultured rat heart cells, and showed a weak antagonistic effect on carbachol-induced adenylate cyclase inhibition, suggesting that it is an M2 antagonist. Using in vivo microdialysis, it was found that relatively low concentrations (<10(-7) M) of SK-946 increased acetylcholine release and decreased choline content in that hippocampal area in rats. These results suggest that SK-946 accelerates muscarinic neuronal transmission in the central nervous system.

Acetylcholine↗

PubMed2007

Pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents.

Solifenacin succinate [YM905; (3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the antimuscarinic properties of solifenacin and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin, propiverine and atropine. In radioligand receptor binding assay, Ki values of solifenacin for human muscarinic M1, M2, M3, M4 and M5 receptors were 26, 170, 12, 110 and 31 nM, respectively. In isolated rat urinary bladder, solifenacin competitively antagonized carbachol-induced contractions, with a pA2 value of 7.44+/-0.09. In these in vitro studies, the antimuscarinic action of solifenacin was more potent than that of propiverine and less potent than those of tolterodine, oxybutynin, darifenacin and atropine. In anesthetized rats, solifenacin and oxybutynin increased the maximum bladder capacity in a dose-dependent manner and also decreased the maximum intravesical pressure. The dosages required to produce a 30% increase in maximum bladder capacity (ED30 values) of solifenacin and oxybutynin were 0.35 and 0.30 mg/kg i.v., respectively, indicating approximately equal efficacies. These results support the fact that solifenacin, similarly to currently used antimuscarinic agents, is an effective agent in the treatment of overactive bladder symptoms such as urinary frequency and urge incontinence.

Animals↗

PubMed1997

[125/123I]IPH: a radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors.

Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [(125)I] or [(123)I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [(125)I]IPH showed substantial brain penetration (4.2% of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs (% injected dose/gram of thalamus, superior colliculi >> cerebellum). [(125)I]IPH binding sites were shown to be saturable with unlabeled IPH (ED50 approximately 1 microg/kg). The uptake of [(125)I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (-)-nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on [(125)I]IPH binding. A preliminary SPECT imaging study with [(123)I]IPH in a baboon showed [(123)I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [(123)I]IPH binding in baboon brain was also displaced (35-45% displacement) by a challenge dose of cytisine showing that a well-characterized nicotinic agonist effectively competes for [(123)I]IPH binding sites. [(123)I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain.

Animals↗

PubMed1997

Synthesis and radiolabeling of (S)-4-amino-5-iodo-2-methoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide, the active enantiomer of [125I]iodozacopride, and re-evaluation of its 5-HT3 receptor affinity.

We report an improved synthesis of unlabeled (S)-iodozacopride, the radiolabeling of (S)-[125I]iodozacopride via deschloro-(S)-zacopride, and a re-evaluation of its affinity for the 5-HT3 receptor. Unlabeled (S)-iodozacopride was prepared in seven steps from 4-aminosalicylic acid via alkaline hydrolysis of its 4-acetamide derivative. Catalytic hydrogenation of (S)-iodozacopride gave deschloro-(S)-zacopride, identical to that obtained from (S)-3-amino-quinuclidine and 4-amino-2-methoxybenzoic acid via its corresponding 1-imidazole derivative. Radioiodination to produce (S)-[125I]iodozacopride was accomplished by treatment of deschloro-(S)-zacopride with 5 mCi sodium 125iodide and chloramine-T in hydrochloric acid. Purification of the reaction products using an HPLC system capable of detecting chlorinated side-products revealed a mixture of 2.1 mCi (1.3 nmol) (S)-[125I]iodozacopride and (S)-zacopride (1.5 nmol). Saturation analysis of the binding of the purified (S)-[125I]iodozacopride to whole rat brain homogenates gave an estimated KD of 1.10 +/- 0.07 nM. As anticipated, this is approximately half the KD reported for binding of racemic [125I]iodozacopride, and differs from the previously reported value by an order of magnitude. Analysis of the apparent binding affinity of a 1:1 mixture of (S)-[125I]iodozacopride and (S)-zacopride suggests that the previous result may have been confounded by contamination of the product with unlabeled (S)-zacopride. Competition analysis of the displacement of (S)-[125I]iodozacopride binding by unlabeled (S)-iodozacopride and (S)-zacopride gave Ki values of 0.95 and 0.21 nM, respectively.

Aminosalicylic Acid↗

PubMed2002

Anti-emetic activity of the novel nonpeptide tachykinin NK1 receptor antagonist ezlopitant (CJ-11,974) against acute and delayed cisplatin-induced emesis in the ferret.

The anti-emetic effects of a novel tachykinin NK(1) receptor antagonist, ezlopitant ((2S,3S-cis)-2-diphenylmethyl)- N-[(2-methoxy, 5-isopropylphenyl)methyl]-1-azabicyclo- [2.2.2]octan-3-amine), were investigated in ferrets. Ezlopitant inhibited [(3)H]substance P ([(3)H]SP) binding to the human, guinea pig, ferret and gerbil NK(1) receptors (K(i) = 0.2, 0.9. 0.6 and 0.5 nmol/l, respectively), but had no affinity to NK(2) and NK(3) receptors up to 1 micromol/l. Ezlopitant also inhibited SP-induced contraction of guinea pig trachea with a pA(2) value of 7.8, but had no effects on the baseline tension and maximum contractile response. In ferrets, ezlopitant, either orally (0.03-3 mg/kg) or subcutaneously (0.3-3 mg/kg), prevented acute retching and vomiting responses induced by intraperitoneal injection of cisplatin (10 mg/kg). In addition, repeated subcutaneous injection of ezlopitant significantly inhibited delayed retching and vomiting responses that occurred in ferrets treated with the lower dose of cisplatin (5 mg/kg, i.p.). Ezlopitant (0.1-1 mg/kg, s.c.) also produced a dose-dependent inhibition of hindpaw tapping induced by intracerebroventricular injection of [Sar(9),Met(O(2))(11)]SP in gerbils, which is known to be mediated by NK(1) receptors in the brain. These findings indicate that ezlopitant is a potent and selective NK(1) receptor antagonist, and that it inhibits both acute and delayed emetic reactions induced by cisplatin in ferrets via acting on NK(1) receptors in the central nervous system.

Animals↗

PubMed1984

Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).

The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.

Anesthesia↗

PubMed1997

Regulation of [3H]norepinephrine release from guinea pig hippocampus by sigma2 receptors.

The binding profile of the sigma2 receptor ligand endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-2,3-dihydro-(1-methyl)eth yl-2-oxo-1H-benzimidazole-1-carboxamidehydrochloride (BIMU-8) had previously been determined, but its agonist/antagonist status at sigma2 receptors had not been identified. We therefore investigated the effects of BIMU-8 for its ability to regulate the stimulated release of [3H]norepinephrine from slices of guinea pig hippocampus. BIMU-8 alone, at a concentration chosen to occupy 50% of sigma2 receptors, had no significant effect on N-methyl-D-aspartate (NMDA)-stimulated release of [3H]norepinephrine. We have shown previously that the sigma receptor agonist (+)-pentazocine inhibits NMDA-stimulated release in a concentration-dependent manner, producing a biphasic inhibition curve. Similarly, the sigma receptor agonist 1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl )cyclohexylamine (BD737) produced a broad inhibition curve. The inhibition by low concentrations of (+)-pentazocine or BD737 that selectively activated sigma1 receptors was reversed by the sigma1-selective receptor antagonist (1-(cyclopropylmethyl)-4-2'-oxoethyl)piperidine HBr (DuP 734). In the current study, when the sigma1 component of inhibition by (+)-pentazocine was blocked by DuP 734, the remaining component of inhibition mediated by sigma2 receptors was reversed by BIMU-8. Our results suggest that (1) BIMU-8 is an antagonist at sigma2 receptors and that (2) sigma2 receptors contribute to regulation of norepinephrine release in guinea pig hippocampus.

Animals↗

PubMed2004

Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment.

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.

Aconitine↗

PubMed1984

2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498): antihypertensive action and persistent inhibition of tissue converting enzyme activity in spontaneously hypertensive rats.

The antihypertensive actions of the new converting enzyme (CE) inhibitors 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl] -L-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and enalapril were compared in spontaneously hypertensive rats (SHRSP), and their effects on tissue CE activity were investigated. Oral treatment with one single dose of the CE inhibitors Hoe 498 (1 mg/kg) and enalapril (30 mg/kg) in normotensive rats produced up to 24 h CE inhibition in plasma, aorta, heart and brain cortex and a 48 h inhibition of the enzyme in kidney and lung. In SHRSP, four-week oral treatment with Hoe 498 (0.1, 1, 10 mg/kg/day) and enalapril (1, 10, 30 mg/kg/day) lowered arterial blood pressure dose-dependently, with normalization of blood pressure following the respective highest dose. Plasma CE activity was inhibited during treatment with both drugs and increased or normal after drug withdrawal, while blood pressure remained decreased for 2-3 weeks post treatment. After 4 weeks of Hoe 498 (3 mg/kg/day) in SHRSP blood pressure was normalized and CE activity was markedly reduced in plasma, lung, kidney, aorta, mesenteric artery, heart, hypophysis and medulla oblongata. The CE inhibition persisted for one week in the kidney and mesenteric artery, accompanying the persistent post treatment blood pressure reduction. Our results demonstrate the strong antihypertensive potency of Hoe 498 in SHRSP and strengthen the hypothesis that CE inhibition in target tissues such as kidney and vascular wall is an important factor involved in the antihypertensive action of CE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Suppressive effect of an inducible nitric oxide inhibitor, ONO-1714, on AOM-induced rat colon carcinogenesis.

The expression of inducible nitric oxide synthase (iNOS) is markedly elevated in rat colon cancers induced by azoxymethane (AOM). In addition, iNOS can be detected in most adenomas and dysplastic aberrant crypt foci (ACF), suggesting that iNOS plays an important role in colon carcinogenesis. In the present study, the effect of an iNOS inhibitor, ONO-1714 ((1S,5S,6R,7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0] heptane hydrochloride), on AOM-induced rat colon carcinogenesis was investigated. Male F344 rats were treated with 15 mg/kg body weight of AOM once a week, for 2 weeks. ONO-1714 was given to the rats at doses of 10, 20, 50, and 100 ppm in diet for 4 weeks from the day before the first carcinogen treatment. The number of AOM-induced ACF in the rats receiving 10, 20, 50 and 100 ppm ONO-1714 were 94, 73 (P < 0.05), 71 (P < 0.005), and 53% (P < 0.0005), respectively, of the control value. Moreover, the mean number of aberrant crypts per focus was significantly lowered in 100 ppm ONO-1714 group (P < 0.05). Then, the effects of long-term treatment (32 weeks) with 50 and 100 ppm ONO-1714 on AOM-induced colorectal tumor development were examined. Although incidences and multiplicities of colon tumors did not significantly differ among the groups, number of tumors developing in the middle part of colon were reduced with both 50 and 100 ppm doses (P < 0.05). Furthermore, colon tumor volume tended to be decreased by ONO-1714 treatment, and the number of colon tumors more than 3mm in diameter was significantly lowered in the 100 ppm ONO-1714 group (P < 0.01). These results suggest that iNOS plays roles in both early and late stages of colon carcinogenesis.

Amidines↗

PubMed1996

GYKI-46 903, a non-competitive antagonist for 5-HT3 receptors.

The effects of GYKI-46 903 ((+)endo-4-propionyloxy-6-(4-fluorophenyl)-1-azabicyclo [3.3.1]non-6-ene HCl), on 5-HT3 receptors have been studied and compared with ondansetron in peripheral organs in vitro and in vivo, and in a receptor binding assay in membranes prepared from rat cerebral cortex. GYKI-46 903 was found to be a non-competitive antagonist at 5-HT3 receptors present in non-stimulated longitudinal muscle strip of guinea-pig ileum (pD2' against serotonin = 5.54), and also in 5-methoxytryptamine-pretreated electrically stimulated ileal preparations (pD2' against serotonin = 5.26). On the contrary, ondansetron was found to be a competitive antagonist for 5-HT3 receptors; the pA2 value against serotonin was 7.40 in non-stimulated ileum, and it was 7.08 in electrically stimulated ileal preparation pretreated with 5-methoxytryptamine. In displacement studies, the pIC50 values of GYKI-46 903 and ondansetron against [3H]granisetron binding to rat cerebral cortex membranes were 6.91 and 8.58 respectively. GYKI-46 903, when administered by intravenous infusion, antagonized the decrease in heart rate evoked by serotonin (Bezold-Jarisch reflex) in anaesthetized rats, and the maximal reversal was less than 50%. This was in striking contrast with ondansetron, which, after intravenous injection, completely antagonized the serotonin-induced bradycardia with an ID50 value of 3.28 ug/kg. These data classify GYKI-46 903 as a non-competitive antagonist for 5-HT3 receptors.

5-Methoxytryptamine↗

PubMed1984

Pharmacokinetics of gliclazide in healthy and diabetic subjects.

The pharmacokinetics of total and free gliclazide, 1-(3-azabicyclo[3,3,0]oct-3-yl)-3-(p-tolylsulfonyl)urea, a potential hypoglycemic drug, was studied in healthy (n = 12) and diabetic (n = 12) subjects. The serum level of gliclazide was determined by a high-performance liquid chromatographic method (HPLC). The free fraction of gliclazide was obtained from serum by an ultrafiltration technique using a collodion membrane. The mean adsorption of gliclazide to the membrane was approximately 50% when the membrane was used more than twice. Therefore, the gliclazide level in the filtrate was corrected by doubling the apparent value. The ratio of gliclazide-protein binding remained constant at approximately 92% in serum after administration to healthy and diabetic subjects. The mean pharmacokinetic parameters of elimination rate (ke), time to reach the peak level (tmax), elimination half-life (t 1/2), and volume of distribution (Vd) were 0.07 h-1, 2.8 h, 12.3 h, and 17.4 L, respectively. The parameters did not differ significantly between healthy and diabetic subjects or between single and successive administrations; moreover, they did not differ between the free and total drug level. Although there were intersubject variations, the therapeutic effects of oral administration of gliclazide on serum glucose and insulin levels were found in four diabetic patients. The results of this study show that the pharmacokinetics of the total gliclazide level reflect those of the free gliclazide in serum.

Adult↗

PubMed1988

General pharmacology of ramipril.

General pharmacological properties of (+)-(1S,3S,5S)-2-[(S)-N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl] alanyl]-2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril, Hoe 498), a new prodrug non-sulfhydryl angiotensin converting enzyme inhibitor and its active diacid metabolite, ramiprilat, were examined. Both ramipril and ramiprilat were without effect on basal central and autonomic nervous systems in rats and mice. Ramipril given intravenously to anaesthetized normotensive dogs produced a slight fall in blood pressure but did not significantly alter other cardio-hemodynamic functions. Also, ramiprilat was without effect on isolated atria and airway resistance of guinea pigs. Oral administration of ramipril to dogs increased renal blood flow but did not significantly affect other renal parameters, for example, glomerular filtration rate and electrolyte excretion. Ramipril produced a competitive inhibition of late proximal tubular secretion which points to in part renal secretory excretion of ramipril and/or its metabolites. Compared to urea-induced diuresis in rats, ramipril was without direct diuretic activity. Ramipril exerted little, if any, influence on gastric bile and pancreatic secretion or intestinal transit in rats, as well as on concentration of glucose and lipoproteins, blood coagulation, platelet aggregation and vascular permeability in rats, rabbits or dogs. The carrageenin-induced rat paw edema was enlarged by ramipril, but there was no such effect on serotonin-, dextran- or ovalbumin-induced edemas which in contrast to carrageenin do not involve bradykinin. Thus, undesired cutaneous reactions might result from locally released bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Identification of SK-951, a novel benzofuran derivative, as an agonist to 5-HT4 receptors.

The pharmacological profile of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl) ethyl]-5-chloro-2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide hemifumarate) was identified in relation to serotonin 5-HT3 and 5-HT4 receptors by the receptor binding assay and functional studies. The receptor binding assay showed that SK-951 bound to the 5-HT3 receptor with a high affinity, to the 5-HT4 receptor with relatively higher affinity and to the muscarinic M2 receptor with a low affinity, but not to dopamine D1 and D2 and serotonin 5-HT1 and 5-HT2 and muscarinic M1 and M3 receptors. SK-951 caused relaxations of tunica muscularis mucosae preparations from rat esophagus which were precontracted with carbachol, and the effects were antagonized by GR113808, a selective 5-HT4 antagonist. In the longitudinal muscle with myenteric plexus (LMMP) preparations from guinea pig ileum, SK-951 enhanced the electrically-stimulated contraction of preparations in which the 5-HT1, 5-HT2 and 5-HT3 receptors were blocked, and it enhanced the electrically-stimulated release of [3H]acetylcholine (ACh). These effects of SK-951 were antagonized by GR113808. SK-951 inhibited the 5-HT3 receptor-mediated contractions. These results indicate that SK-951 possesses properties of an agonist for the 5-HT4 receptor and an antagonist for the 5-HT3 receptor. Thus, SK-951 is a new and potent 5-HT4-receptor agonist and causes contractions of guinea pig ileum mediated by enhancement of ACh release via the 5-HT4 receptor.

Acetylcholine↗

PubMed2000

The acute and subchronic toxicity of BRB-I-28, a novel class Ib antiarrhythmic agent, in CD-1 mice.

The acute and subchronic toxic effects of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane HCl), a novel class Ib antiarrhythmic agent, were investigated in male and female mice. The estimated oral LD(50) for BRB-I-28 was 128 mg/kg (male mice) and 131 mg/kg (female mice). In subchronic oral studies, four groups of mice (15/sex/group/dose) were fed daily with diets containing BRB-I-28 for 90 consecutive days. The equivalent daily doses were approximately 0, 16, 32, 76 (male) and 0, 18, 37, 89 mg/kg (female). All mice survived. Food consumption per day was decreased, but water consumption per day was increased (in a non-dose-dependent manner). However, both mean body weight and mean body weight gain were not significantly changed as were true for hematological and clinical chemistry profiles, except for serum Na(+) concentration (male) and serum K(+) concentration in male and female mice (high dose levels). Hepatocellular necrosis occurred in male and female mice (in a dose-dependent fashion). Renal cortical vacuoles and myocardial necrosis with low numbers of lymphocytic infiltrations were present in female mice (middle and high doses). Lesions in the liver, kidney and heart were mild with (very small) changes in serum biochemical values. These data suggest that BRB-I-28 has limited toxic potential, and coupled with low proarrhythmic and other desirable cardiovascular effects, makes BRB-I-28 worthy of further development.

Animals↗