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PubMed2003

Dopamine receptor ligands. Part VII [1]: novel 3-substituted 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles as ligands for the dopamine receptors.

A number of 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles 3 were synthesized with different substituents at the azepine-N position (methyl-, allyl-, 2-phenyl-ethyl-, cyclopropylmethyl- and unsubstituted). Furthermore, the indole-N-methylated compound was generated and by using norephedrines and norpseudoephedrines as a chiral pool, 4-methyl-5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles were prepared which contained racemisation at the reacting C-atom. These compounds, as well as the ring-open amino-alcohols, were screened for their affinity to the hD(1)-, hD(5)-, hD(2L)-, and hD(4)-receptors (ç please check sentence). They had micromolar affinities for the receptors and showed the highest affinity to the D(1)-subtype family. The cyclic compounds possessed the highest affinity, with the cyclopropylmethyl-(3c) and methyl-substituents (3 e) being the most active of the tested compounds. Based on an intracellular cAMP-assay, the unsubstituted compound (at the azepine-N position) turned out to be an agonist for the D(1)-and D(5)-subtype family, whereas the substituted compounds showed (partial) agonistic, or even inverse agonistic activity.

Animals↗
PubMed1986

Dermal penetration enhancement profile of hexamethylenelauramide and its homologues: in vitro versus in vivo behavior of enhancers in the penetration of hydrocortisone.

Several amides of cyclic amines were prepared and tested as penetration enhancers in the diffusion of various drugs through hairless mouse skin in vitro. Hexamethylenelauramide (hexahydro-1-lauroyl-1H-azepine) was selected as a broad spectrum penetration enhancer worthy of further study. Later, the duration of the effect of various enhancers on the penetration barrier in vivo was determined by evaluating the in vitro diffusion of hydrocortisone through skins that had been pretreated in vivo. We found that the longer the pretreatment, the smaller the amount of penetrated hydrocortisone. Furthermore, our results suggested that differences exist in the retention of various enhancers in living mouse skin. The in vitro pretreatment experiments revealed that the penetration through dead skin is slow compared with the penetration through living skin. Neither the nature of the receptor phase, nor the increased temperature of the in vitro experiments, explain the striking differences between the in vivo and the in vitro experiments. Finally, the penetration of hydrocortisone through the stratum corneum in the presence of enhancers, as well as the penetration of 1-dodecylhexahydro-2H-azepin-2-one (laurocapram), hexamethylenelauramide, and oleic acid, were determined using a stratum corneum stripping technique. More hydrocortisone penetrated through the stratum corneum during the first 3 h in the presence of hexamethylenelauramide than in the presence of laurocapram or oleic acid.

Animals↗
PubMed1985

Differential modulation of gamma-aminobutyric acid receptors by caprolactam derivatives with central nervous system depressant or convulsant activity.

The effects of a series of caprolactam derivatives with central depressant, convulsant or muscle relaxant activity were investigated upon gamma-aminobutyric acid (GABA) receptor-ionophore binding to rat brain membranes using [3H]GABA, [3H]GABA, [3H]muscimol and [35S]-tert.-butylbicyclophophorothionate ([35S]TBPS) as ligands, and GABA responses in mouse spinal cord neurones in dissociated cell culture. Some caprolactams produced a picrotoxin-like chloride-dependent partial inhibition of muscimol binding and were potent inhibitors of TBPS binding. One compound that was further investigated (4,4,6,6-tetramethylhexahydro-2H-azepin-2-one), inhibited GABA responses and increased the frequency of paroxysmal depolarizations in cultured neurones. Other caprolactams enhanced muscimol binding and were relatively weak inhibitors of TBPS binding, and one (3,3-diallyl-6,6-dimethylhexahydro-2H-azepin-2,4-dione) was shown to enhance GABA responses and produced quiescence of activity in cultured neurones. There was a direct correlation between caprolactam effects on muscimol binding in the presence of chloride ions and their effects on TBPS binding suggesting a similar site of action for the caprolactams influencing the binding of these two ligands. For the two classes of caprolactams, with respect to inhibition or enhancement of muscimol binding, there appeared to be a relationship between in vitro effects and their convulsant or depressant activity in mice. Caprolactams may be useful low molecular weight probes for the study of GABA receptor-ionophore complexes.

Animals↗
PubMed1980

Binding of an imidazolidine (clonidine), an oxazoloazepin (B-HT 933) and a thiazoloazepin (B-HT 920) to rat brain alpha-adrenoceptors and relation to cardiovascular effects.

The specific binding to alpha-adrenoceptors in crude plasma membrane preparations of the rat brain was studied by means of 3H-clonidine (specific radioactivity 26.7 Ci/mmole). Equilibrium binding of 3H-clonidine could be described adequately according to a two-site model with a minor population of high affinity sites (KD1 = 0.4 nM) and a major population of low affinity sites (KD2 = 6.1 nM). The heterogeneity of 3H-clonidine binding was also indicated by a biphasic association rate in kinetic binding studies. In competition experiments with 3H-clonidine concentrations of 0.5 or 4.0 nM respectively, concentration-dependent displacement was observed with the non-radioactive compounds: clonidine, B-HT 920 (2-amino-6-allyl-5, 6, 7, 8-tetrahydro-4H-thiazolo-[5, 4-d]-azepin-dehydrochloride) and B-HT 933 (2-amino-6-ethyl-4, 5, 7, 8-tetrahydro-6H-oxazolo-[5, 4-d]-azepin-dihydrochloride). IC50 values of 3, 21 and 160 nM or 10, 63 and 380 nM respectively were thereby evaluated. Cardiovascular effects were estimated in rats. The blood pressure increase in spinal animals was taken as parameter for alpha-adrenoceptor stimulation at peripheral vascular sites. The bradycardic effect in vagotomized animals was taken as parameter for central nervous sympathoinhibition. The ranking order of the potency of the three drugs was the same in both in vivo tests and parallels the in vitro binding affinities at both binding sites: clonidine greater than B-HT 920 greater than B-HT 933. These results indicate the similarity of the alpha-adrenoceptor structures in brain membrane preparations, at peripheral vascular sites and at central sympathoinhibitory sites.

Animals↗
PubMed1997

Talipexole or pramipexole combinations with chloro-APB (SKF 82958) in MPTP-induced hemiparkinsonian monkeys.

The effects of two predominant dopamine D2-like receptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine dihydrochloride, B-HT 920 CL2) and pramipexole (S(-)2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzothiazole dihydrochloride, SND 919 CL2Y), were studied alone and in combination with the selective dopamine D1-like receptor agonist chloro-APB ((+/-)6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benz azepine hydrobromide, SKF 82958) in five chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotation in a dose-dependent manner up to 32 microg/kg, i.m. Talipexole was more potent than pramipexole (10 vs. 32 microg/kg, i.m.), but pramipexole was more efficacious in producing contraversive rotational behavior and significant hand movements in the afflicted limb. Larger doses of chloro-APB also produced contraversive rotation. Combinations of each dopamine D2-like receptor agonist in a median effective dose with chloro-APB (23.4 and 74.8 microg/kg, i.m.) had synergistic effects, producing either addition or potentiation, depending upon the dose used. The effects noted with these combinations were less than the effect of a large dose (100 microg/kg) of pramipexole. Talipexole, in the largest dose studied (100 microg/kg, i.m.), produced sedation which was not seen with the same dose of pramipexole. No significant extrapyramidal side effects were noted with either agent.

Animals↗
PubMed2003

Spiro cross-links: representatives of a new class of glycoxidation products.

Covalently cross-linked proteins are among the major modifications caused by the advanced Maillard reaction. So far, the chemical nature of these aggregates is largely unknown. Investigations are reported on the isolation of 6-[2-[[(4S)-4-amino-4-carboxybutyl]amino]-6,7-dihydroxy-6,7-dihydroimidazo[4,5-b]azepin-4(5H)-yl]-L-norleucine (10) and N-acetyl-6-[(6R,7R)-2-[[4-(acetylamino)-4-carboxybutyl]amino]-6,7,8a-trihydroxy-6,7,8,8a-tetrahydroimidazo[4,5-b]azepin-4(5H)-yl]-L-norleucine (12) formed by oxidation of the major Maillard cross-link glucosepane 1. Independent synthesis and unequivocal structural characterization are given for 10 and 12. Spiro cross-links, representing a new class of glycoxidation products, were obtained by dehydrogenation of the amino imidazolinimine compounds N6-[2-[[(4S)-4-ammonio-5-oxido-5-oxopentyl]amino]-5-[(2S,3R)-2,3,4-trihydroxybutyl]-3,5-dihydro-4H-imidazol-4-ylidene]-L-lysinate (DOGDIC 2) and N6-[2-[[(4S)-4-ammonio-5-oxido-5-oxopentyl]amino]-5-[(2S)-2,3-dihydroxypropyl]-3,5-dihydro-4H-imidazol-4-ylidene]-L-lysinate (DOPDIC 3). These new oxidation products were synthesized, and their unambiguous structural elucidation proved the formation of the spiro imidazolimine structures N6-[(7R,8S)-2-[[(4S)-4-ammonio-5-oxido-5-oxopentyl]amino]-8-hydroxy-7-(hydroxymethyl)-6-oxa-1,3-diazaspiro[4.4]non-1-en-4-ylidene]-L-lysinate (16), N6-(8R,9S)-2-[(4S)-4-ammonio-5-oxido-5-oxopentyl]amino]-8,9-dihydroxy-6-oxa-1,3-diazaspiro[4.5]dec-1-en-4-ylidene)-L-lysinate (19), and N6-[(8S)-2-[(4-amino-4-carboxybutyl)amino]-8-hydroxy-6-oxa-1,3-diazaspiro[4.4]non-1-en-4-ylidene]-L-lysinate (18), respectively. It was shown that reaction of the imidazolinone 15 led to the formation of spiro imidazolones, structurally analogous to 16 and 19.

Azepines↗
PubMed2001

Synthesis and structure-activity relationships of cetiedil analogues as blockers of the Ca(2+)-activated K+ permeability of erythrocytes.

Cetiedil, [2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethyl ester], which blocks the intermediate calcium-activated potassium ion permeability (IK(Ca)) in red blood cells, was used as a lead for investigating structure-activity relationships with the aim of determining the pharmacophore and of synthesizing agents of greater potency. A series of compounds having structures related to cetiedil was made and tested on rabbit erythrocytes. Channel blocking activity within the series was found to correlate well with octanol-water partition coefficients but not with the specific chemical structure of the acid moiety. However, whereas log P for the compounds spans a range of values over 4 orders of magnitude, potency only increases by 2 orders. This suggests that hydrophobic interactions with an active site on the channel are probably not the main determinants of activity. It seems more likely that increased lipophilicity enhances access to the channel, probably from within the cell membrane. In keeping with this interpretation, cetiedil methoiodide was found to be inactive. Triphenylethanoic was found to be a more effective acid grouping than 2-cyclohexyl-2-(3-thienyl)ethanoic, and its 2-(hexahydro-1H-azepin-l-yl)ethyl ester (11) was approximately 3 times more potent than cetiedil. The 9-benzylfluoren-9-yl carboxylic acid ester (21) was found to be approximately 9 times more active than cetiedil, and replacing -CO(2)- in 21 by an ethynyl (-C identical to C-) linkage (compound 26, UCL 1608) increased potency by some 15-fold over that of cetiedil.

Animals↗
PubMed1997

Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.

In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.

Azepines↗
PubMed2001

Asymmetric synthesis of 2-alkyl-perhydroazepines from [5,3,0]-bicyclic lactams.

The synthesis and utility of a novel class of [5,3,0]-bicyclic lactams are described. Produced by the cyclodehydration of (R)-phenylglycinol with omega-keto acids, lactams 4-6 were obtained as separable diastereomeric mixtures ( approximately 2:1) in low yields ( approximately 40%). Higher chemical yield (up to 61%) was realized via an alternate route involving ring closure metathesis of 2-allyl-N-acroyl oxazolidines, 8. Stereoselective reductions of the syn-bicyclic lactams, 4a and 5a, occurred with the use of alane or lithiumaluminum hydride, affording azepine alcohols, 11a and 15a, of the R configuration at the 2-position, in good to moderate yields (50-88%). High selectivity was also observed in the diisobutylaluminum hydride reduction of the epimeric anti lactams, 4b and 5b, affording azepine alcohols, 11b and 15b, of the S configuration at C-2. Hydrogenolytic cleavage of the N-benzyl moiety afforded chiral 2-substituted perhydroazepines, (R)- and (S)-12, in good yields and good enantiomeric excesses (84-94%).

Azepines↗
PubMed1991

The guinea-pig ileum preparation as a model for 5-HT1A receptors: anomalous effects with RS-30199-193.

1. Agents that have high and selective affinity for the 5-HT1A site such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and N,N-dipropyl-5-carboxamidotryptamine (DP5CT) inhibited the responses to field stimulation in guinea-pig ileum preparations; the inhibitory effects were antagonized by methiothepin and spiperone, consistent with effects at the 5-HT1A site. 2. The inhibitory effects of DP5CT were pronounced in Tyrode solution containing low Ca2+ (0.9 mM), but were much less apparent in Tyrode solution containing 1.8 or 5.4 mM Ca2+. 3. Responses to DP5CT were abolished by pretreatment with phorbol dibutyrate (3 microM), whereas the responses to UK14304 were only slightly inhibited. 4. Buspirone and ipsapirone (1 microM) inhibited the responses to field stimulation, and the effects were resistant to idazoxan, but inhibited by 8-OH-DPAT or spiperone. 5. RS-30199-193 (5-chloro-2-methyl-1,2,3,4,8,9,10,10a-octahydronaphth-[1,8-cd]- aze pine hydrochloride) an azepine with high affinity for the 5-HT1A site in rat cerebral cortex in binding experiments, augmented contractions, but did not antagonize the responses to DP5CT or to 8-OH-DPAT. 6. The hybrid compound of RS-30199-193 with buspirone, RS-64459-193 (5-chloro-2-[4-(8-azaspiro[4,5]decane-7,9-dione)-but-1-yl]- 1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]-3-azepine hydrochloride) maintained high affinity for the 5-HT1A binding site in rat brain and both inhibited the response to field stimulation and antagonized the responses to 8-OH-DPAT and DP5CT. Thus the buspirone side chain when added to RS-30199-193 appears either to induce affinity for a distinct subset of receptors in the guinea-pig ileum or is required for functional effectiveness at the 5-HTlA receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Synthesis of new N-containing maltooligosaccharides, alpha-amylase inhibitors, and their biological activities.

Fifteen new N-containing maltooligosaccharides were obtained using the chemoenzymatic method. Among these compounds, maltooligosaccharides having 6-amino-6-deoxy-D-sorbitol residue, (3R,4R,5R,6S)-hexahydro-3,4,5,6-tetrahydroxy-1H-azepine residue, and (3R,5R)-3,4,5-trihydroxypiperidine residue at the reducing end showed strong inhibitory activities for human pancreatic alpha-amylase (HPA) (EC 3.2.1.1) and human salivary alpha-amylase (HSA). The administration of (3R,4R,5R,6S)-hexahydro-3,5,6-trihydroxy-1H-azepine-4-yl O-alpha-D-glucopyranosyl-(1-->4)-alpha-D-glucopyranoside (13, IC50 = 4.3 x 10(-5) M for HPA, IC50 = 8.2 x 10(-5) M for HSA) and (3R,5R)-3,5-dihydroxypiperidine-4-yl O-alpha-D-glucopyranosyl-(1-->4)-alpha-D-glucopyranoside (18, IC50 = 3.4 x 10(-5) M for HPA, IC50 = 4.6 x 10(-5) M for HSA) to ICR mice suppressed postprandial hyperglycemia.

Animals↗
PubMed1999

Synthesis and pharmacological evaluation of pyrroloazepine derivatives as potent antihypertensive agents with antiplatelet aggregation activity.

A series of 1-aminoalkyl-pyrrolo[2,3-c]azepin-8-one derivatives was synthesized and evaluated as alpha 1 adrenergic and serotonin 2 (5-HT2) receptor antagonists, with the aim of finding a novel antihypertensive agent potently exhibiting both activities. Some compounds with a 4-[4-(4-fluorobenzoyl)piperidino]butyl group at the 1-position exhibited both activities, and varied significantly in terms of the substituents at the 4-position of the pyrroloazepine ring. Among the compounds obtained in this study, (E)-1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-4-hydroxyimino-7- methyl-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-one (15a, SUN9221) displayed potent alpha 1-adrenergic antagonistic activity (pA2 = 8.89 +/- 0.21) and 5-HT2 antagonistic activity (pA2 = 8.74 +/- 0.22) in isolated guinea pig arteries. This compound exhibited antihypertensive activity and a duration of action equivalent to orally administered prazosin or doxazosin, 3 mg/kg, in conscious spontaneously hypertensive rats, as well as potent antiplatelet aggregation activity.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

Synthesis of tricyclic compounds as steroid 5alpha-reductase inhibitors.

A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skeleton were prepared and evaluated as 5alpha-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymis (type 2) 5alpha-reductase inhibitory activities reveal that 1) the substitution pattern at the 11-position of dibenz[b,e]oxepin influenced potency, 2) higher lipophilicity of the tricyclic skeleton improved potency, whereas the existence of a basic nitrogen atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at the 8 positon of the azepine skeleton was tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10,11-dihydrodibenz[b,f]azepine- 2-carboxamido]phenoxy]butyric acid (26) was the most potent inhibitor of rat type 2 5alpha-reductase at 0.1 microM.

5-alpha Reductase Inhibitors↗
PubMed1997

Synthesis and chiroptical properties of a novel C2-symmetric binaphthyl phosphortriamide ("chiral HMPA").

By use of an asymmetric Ullmann coupling involving chiral naphthalene oxazolines 1, the title compounds were prepared in good yields and with high diastereoselectivity. Hydrolysis of the binaphthyl oxazolines 2 led to the di-aldehydes 5, which were transformed into the azepine derivative, 6. The latter was treated with the appropriate phosphoryl halide to access the chiral HMPA systems 7 and 9. The CD spectra of the chiral azepine 6 and the chiral phosphoramides 7 and 9 were measured and showed a strong positive CD couplet near 225 nm, consistent with the P axial chirality (S configuration). Semi-empirical CNDO/S molecular orbital calculations of the CD spectrum of 6 satisfactorily reproduced the major features of the observed spectrum.

Circular Dichroism↗
PubMed1982

In vitro skin evaporation and penetration characteristics of mosquito repellents.

An in vitro apparatus was used to study mosquito repellent evaporation and penetration characteristics with skin. The mosquito repellents 2-ethyl-1,3-hexanediol, N,N-diethyl-m-toluamide, N,N-diethyl-p-toluamide, 1-(butylsulfonyl)hexahydro-1H-azepine, and N,N'-dicyclohexamethyleneurea were studied. In vitro repellent duration, calculated from repellent evaporation rates, was compared to in vivo duration at the same dose (0.3 mg/cm2) to assess the validity of the model. In vitro durations for 2-ethyl-1,3-hexanediol, N,N-diethyl-m-toluamide, N,N-diethyl-p-toluamide, and N,N'-dicyclohexamethyleneurea correlated with in vivo durations (r2 = 0.94), although in vitro durations was longer than in vivo duration. 1-(Butylsulfonyl)hexahydro-1H-azepine, which had the longest in vivo duration, had an in vitro duration that exceeded the test period (12 hr). The 0-12-hr in vitro percutaneous penetration correlated with corresponding data available from in vivo studies.

Aedes↗
PubMed1987

Imipramine treatment alters the pharmacokinetics and pharmacodynamics of diazepam.

This report describes observations of the relationship between the pharmacokinetics and pharmacodynamics of diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ; 5 mg/kg) during the concomitant administration of diazepam and imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride; 20 and 50 mg/kg) to rats. We measured plasma, brain, and liver concentrations of diazepam and its metabolites in rats by high-performance liquid chromatography. The concomitant use of imipramine hydrochloride increased diazepam and desmethyldiazepam concentrations, but decreased temazepam and oxazepam concentrations in rat plasma. Diazepam plasma protein binding was unaltered. The liver concentrations of diazepam and its metabolites showed similar changes in their plasma concentrations. The concomitant use of imipramine hydrochloride increased the concentrations of diazepam and its metabolites in the brain. We also studied the effect of benzodiazepines on convulsions induced by pentylenetetrazole (6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a] azepine; 135 mg/kg) in rats. The concomitant use of imipramine hydrochloride led to an increased antipentylenetetrazole effect of diazepam. This result is in accordance with the findings on brain concentrations of diazepam and its metabolites.

Animals↗
PubMed1989

Pharmacokinetic study of iminodibenzyl antipsychotic drugs, clocapramine and Y-516 in dog and man.

The pharmacokinetic properties of the iminodibenzyl antipsychotic drugs clocapramine (CCP, 3-chloro-5-[3-(4-carbamoyl-4-piperidino piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) and Y-516 (3-chloro-5-[3-(2-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydroimidazo [1,2-a] pyridine-3-spiro-4'-piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) were investigated in dog and man. Dogs were administered CCP and Y-516 intravenously, intraperitoneally, and orally, and the concentrations of the parent drugs and their metabolites in the plasma and urine were determined. Half-life (t1/2) was approximately the same by all three administration routes, being approximately 5 h for CCP and 3 h for Y-516. Bioavailability following oral administration was 0.16 +/- 0.01 (mean +/- SD, n = 3) for CCP and 0.29 +/- 0.07 for Y-516. The fractions of dose absorbed following oral administration were 0.43 +/- 0.07 and 0.79 +/- 0.24, and the fractions of dose metabolized in the liver due to the first-pass effect were 0.63 +/- 0.05 and 0.63 +/- 0.04 for CCP and Y-516, respectively. Y-516 was detected in the plasma after intraperitoneal and oral administration of CCP. The ratio of the AUC of Y-516 to that of CCP was 0.06 following intraperitoneal administration and 0.40 following oral administration. This indicated that while the metabolism of CCP into Y-516 may occur partly in the liver due to the first-pass effect, it occurs mostly within the gastrointestinal tract itself or its mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Diminished alpha 2-adrenoceptor-mediated modulation of noradrenergic neurotransmission in the posterior hypothalamus of spontaneously hypertensive rats.

An azepine derivative, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine (B-HT 920; 100 nM), inhibited the evoked noradrenaline release from slices of rat posterior hypothalamus, and yohimbine (100 nM) potentiated the release from slices of rat anterior and posterior hypothalamus. In the posterior hypothalamus of 4- and 15-16-week-old spontaneously hypertensive rats (SHRs), as compared with age-matched Wistar-Kyoto rats (WKYs), the inhibitory effect of B-HT 920 and the facilitatory effect of yohimbine were decreased. In the anterior hypothalamus there was no significant difference in the yohimbine effect between WKYs and SHRs, at either age. It is concluded that alpha 2-adrenoceptor-mediated autoinhibition of noradrenergic neurotransmission is diminished in the posterior hypothalamus of SHRs.

Animals↗