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PubMed1992

Benzimidazolone derivatives act as 5-HT4 receptor ligands in rat oesophagus.

Three benzimidazolone derivatives have been evaluated in the tunica muscularis mucosae preparation of the rat oesophagus for activity at the 5-HT4 receptor. BIMU 1 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyl-2-ox o- 1H-benzimidazole-1-carboxamide HCl) and BIMU 8 (endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl)eth yl- 2-oxo-1H-benzimidazole-1-carboxamide HCl) acted as potent but partial agonists relative to 5-HT whereas DAU 6215 (N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)2,3-dihydro-2-oxo-1H- benzimidazole-1-carboxamide HCl) behaved as a competitive antagonist with a pA2 of 6.5. The pEC50 values for BIMU 1 and BIMU 8 were 8.0 and 7.9, respectively, compared with 8.2 for 5-HT. Intrinsic activity values were 0.7 and 0.9, respectively. BIMU 1 and BIMU 8 are the most potent synthetic agonists so far tested in rat oesophagus, and DAU 6215 exhibits an equivalent affinity to ICS 205 930 at the 5-HT4 receptor.

Animals↗

PubMed2000

Cheletropic decomposition of cyclic nitrosoamines revisited: the nature of the transition states and a critical role of the ring strain.

The cheletropic decompositions of 1-nitrosoaziridine (1), 1-nitroso-Delta(3)-pyrroline (2), 7-nitroso-7-azabicyclo[2.2. 1]hepta-2,5-diene (3), and 6-nitroso-6-azabicyclo[2.1.1]hexa-4-ene (4) have been studied theoretically using high level ab initio computations. Activation parameters of the decomposition of nitrosoaziridine 1 were obtained experimentally in heptane (DeltaH()(298) = 18.6 kcal mol(-)(1), DeltaS()(298) = -7.6 cal mol(-)(1) K(-)(1)) and methanol (20.3 kcal mol(-)(1), 0.3 cal mol(-)(1) K(-)(1)). Among employed theoretical methods (B3LYP, MP2, CCD, CCSD(T)//CCD), the B3LYP method in conjunction with 6-31+G, 6-311+G, and 6-311++G(3df,2pd) basis sets gives the best agreement with experimental data. It was found that typical N-nitrosoheterocycles 2-4 which have high N-N bond rotation barriers (>16 kcal mol(-)(1)) extrude nitrous oxide via a highly asynchronous transition state with a planar ring nitrogen atom. Nitrosoaziridine 1, with a low rotation barrier (<9 kcal mol(-)(1)) represents a special case. This compound can eliminate N(2)O via a low energy linear synperiplanar transition state (DeltaH()(298) = 20.6 kcal mol(-)(1), DeltaS()(298) = 2.5 cal mol(-)(1) K(-)(1)). Two higher energy transition states are also available. The B3LYP activation barriers of the cheletropic fragmentation of nitrosoheterocycles 2-4 decrease in the series: 2 (58 kcal mol(-)(1)) >> 3 (18 kcal mol(-)(1)) > 4 (12) kcal mol(-)(1). The relative strain energies increase in the same order: 2 (0 kcal mol(-)(1)) << 3 (39 kcal mol(-)(1)) < 4 (52 kcal mol(-)(1)). Comparison of the relative energies of 2-4 and their transition states on a common scale where the energy of nitrosopyrroline 2 is assumed as reference indicates that the thermal stability of the cyclic nitrosoamines toward cheletropic decomposition is almost entirely determined by the ring strain.

Aziridines↗

PubMed1996

7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonane 3-oxide.

The molecular geometry of a major metabolite, C14H19NOS, of a potent anti-arrhythmic drug, 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane (BRB-I-28), has been determined by X-ray diffraction. The 3,7-dihetero bicyclic system of the sulfoxide molecule adopts a chair--chair conformation like that of the HCLO4 salt of the BRB-I-28 molecule. The S...N contact distance of 2.863(2)A in the present molecule is significantly shorter than that found in the crystal structure of its precursor [3.038(4)A]. The overall molecule possesses pseudo-mirror symmetry.

Anti-Arrhythmia Agents↗

PubMed2005

Design, synthesis, and application of azabicyclo[X.Y.0]alkanone amino acids as constrained dipeptide surrogates and peptide mimics.

Azabicyclo[X.Y.0]alkanone amino acids are challenging synthetic targets and useful tools for studying structure-activity relationships of native peptide ligands. They have been employed to increase potency and stability in conformationally rigid enzyme inhibitors and receptor ligands. Since last reviewed in 1997, activity in their synthesis and application has increased significantly and access is now available to a wider diversity of these peptide mimics. This review focuses on recent syntheses of these heterocyclic amino acids and their application in the investigation of biologically active peptides and peptide mimics.

Amino Acids↗

PubMed2000

Synthesis of enantiopure 1-azabicyclo[3.2.2]nonanes via stereoselective capture of chiral carbocations.

[reaction: see text] A new class of doubly functionalized and enantiomerically pure 1-azabicyclo[3.2.2]nonanes derived from quincorine and quincoridine is described. 2,5-Disubstituted quinuclidines with a C9-mesyloxy group were easily transformed into the corresponding halides upon treatment with lithium salts. Subsequent silver salt-mediated ring expansion stereoselectively furnished the title azabicyclics. Chiral carbocations which are configurationally stable and nonplanar are postulated to account for the striking stereoselectivity of the capture of external nucleophile. 5-Ethynyl-2-iodomethylquinuclidines afford the alpha-benzoyloxy amines rather than alpha-methoxy amines, even in MeOH.

Amines↗

PubMed2002

Preparation of a bromine-76 labelled analogue of epibatidine: a potent ligand for nicotinic acetylcholine receptor studies.

Epibatidine analogues have been labelled with I-123 for single photon emission computed tomography and with short half-life positron emitters (C-11 and F-18) for PET. For easier radiopharmacological studies the bromo analogue of epibatidine (norchlorobromoepibatidine or exo-7-azabicyclo-2-(2-bromo-5-pyridyl)-[2.2.1]heptane) was labelled with Br-76, a longer half-life positron emitter, (T1/2 = 16.2h). [76Br]-norchlorobromoepibatidine was prepared by using a Cu+ assisted bromodeiodination exchange from the iodo analogue in reducing conditions at 190 degrees C. The tracer purified by RP-HPLC was obtained in 70% radiochemical yield with a specific radioactivity of 20 GBq/micromol. Radiochemical and chemical purities measured by radio-TLC and HPLC were >98%.

Animals↗

PubMed1996

Stereochemistry of serotonin receptor ligands from crystallographic data. Crystal structures of NAN-190.HBr, 1-phenylbiguanide, MDL 72222 and mianserin.HCl and selectivity criteria towards 5-HT1, 5-HT2, and 5-HT3 receptor subtypes.

The crystal and molecular structures of the following serotoninergic drugs have been determined: (1) 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide hemihydrate (NAN-190.HBr), C23H28N3O3+.Br-.1/2H2O, M(r) = 483.42, monoclinic, C2/c, a = 21.916 (4), b = 15.207 (2), c = 14.052 (2) A, beta = 101.56 (1) degree, V = 4588 (1) A3, Z = 8, Dx = 1.40 Mgm-3, lambda (Mo K alpha) = 0.71069 A, mu = 1.823 mm-1, F(000) = 2008, T = 295 K, R = 0.035 for 2617 observed reflections; (2) N-phenylimidocarbonimidic diamide (1-phenylbiguanide), C8H11N5, M(r) = 177.21, monoclinic, P2(1)/c, a = 9.781 (2), b = 35.040(5), c = 11.000 (2) A, beta = 97.72(1) degree, V = 3736(1)A3, Z = 16, Dx = 1.26 Mg m-3, lambda (Mo K alpha) = 0.71069 A, mu = 0.084 mm-1, F(000) = 1504, T = 295 K, R = 0.070 for 3407 observed reflections; (3) 8-methyl-8-azabicyclo[3.2.1]oct-3yl 3,5-dicholorobenzoate (MDL 72222), C15H17Cl2NO2, M(r) = 314.21, triclinic, P1, alpha = 8.480 (3), b = 9.840 (3), c = 10.158 (4) A, alpha = 90.04 (3), beta = 111.77 (3), gamma = 105.07(3) degrees, V = 755.6(5) A3, Z = 2, Dx = 1.38 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.430 mm-1, F(000) = 328, T = 295 K, R = 0.070 for 1685 observed reflections; (4) 1, 2, 3, 4, 10, 14b-hexahydro-2-methyldibenzo[c.f]pyrizino[1, 2-alpha]azepine hydrochloride (mianserin. HCl), C18H21N2+. Cl-, M(r) = 300.83, monoclinic, P2(1)/a, a = 9.014 (2), b = 14.917 (2), c = 12.412 (2) A, beta = 108.84 (1) degree, V = 1579.5 (5) A3, Z = 4, Dx = 1.26 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.237 mm-1, F(000) = 640, T = 295 K, R = 0.063 for 1493 observed reflections. A systematic structural analysis of the present compounds and others known to interact with the 5-HT1, 5-HT2 and 5-HT3 receptors allows to identify their similarities with the endogenous ligand serotonin (5-HT) and the stereochemical differences which determine selectivity for the various receptor subtypes. The pharmacophoric feature for 5-HT receptor binding is identified in a constant-length vector linking an aromatic ring with a protonated nitrogen, while specific affinities for receptorial subtypes and the nature of the effect appear to be modulated by the dimensions of the substituents at nitrogen.

Biguanides↗

PubMedDate not supplied

TLC resolution of enantiomers of amino acids and dansyl derivatives using (1R,3R,5R)-2-azabicyclo[3,3,0]octan-3-carboxylic acid as impregnating reagent.

The enantiomeric resolution of certain amino acids and some of their dansyl derivatives was achieved on thin silica gel plates impregnated with (1R,3R,5R)- 2-Azabicyclo[3,3,0]octan-3-carboxylic acid, which is an industrial waste material, and a proline analogue non proteinogenic alpha-amino acid. Different combination of 0.5 M NaCl-MeCN were found to be successful in resolving dansyl-DL-amino acids; addition of methanol was required in some cases. Spots were visualised using a fixed wavelength (254 nm) ultraviolet chamber. Resolution of DL-amino acids was successful in different combinations of MeCN-MeOH-H2O and detection was made with ninhydrin (0.2% in acetone).

Amino Acids↗

PubMed2001

Poly-L-proline type II peptide mimics based on the 3-azabicyclo[3.1.0]hexane system.

This paper describes conformational studies of proline-templated amino acids (PTAAs) based on the 3-azabicyclo[3.1.0]hexane system as well as conformational studies on short peptides composed of these PTAAs. NOE data, coupling constants, and molecular modeling are consistent with a flattened boat conformation for monomeric and oligomeric residues based on this bicyclic system. NMR studies on dimeric and trimeric oligomers are consistent with a populated poly-L-proline type II conformation in CDCl3 and D2O. Solution studies and molecular modeling predicts phi approximately -70 degrees, psi approximately 131 degrees, chi 1 approximately -57 degrees, and chi 2 approximately -158 degrees for oligomeric residues.

Bridged Bicyclo Compounds, Heterocyclic↗

PubMed1985

The metabolism of gliclazide in man.

Gliclazide, 1-(3-azabicyclo[3,3,0]oct-3-yl)-3-(4-methylphenylsulphonyl)urea, was orally administered to five healthy male volunteers at a dose of 40 mg. Urine contained seven metabolites classified into two types according to the site of biotransformation. Two major metabolites, 1-(3-azabicyclo[3,3,0]oct-3-yl)-3-(4-carboxyphenylsulphonyl)urea and 1-(3-azabiyclo[3,3,0]oct-3-yl)-3-(4-hydroxymethyl-phenylsulphon yl)urea, of the first type were oxidized at the methyl group of the tolyl group. Five metabolites of the second type including two glucuronides were hydroxylated at a specific site in the azabicyclo-octyl ring (b beta, 7 beta and 7 alpha). The molecular conformation of this type of metabolites could explain the existence of conjugates of the beta-hydroxy groups in the azabicyclo-octyl ring and the absence of those of the alpha-hydroxy group. Only the unchanged drug was detected in plasma. The peak concentration at four hours after dosing was 2.6 +/- 0.2 microgram/ml, and the elimination half-life in plasma was 8.1 +/- 1.1 hours which was apparently determined by the rate of metabolism. Identified metabolites excreted in urine accounted for 45% of the dose in 24h and 61% in 96h, indicating that this was the major excretory route.

Adult↗

PubMed2002

Complex-induced proximity effects. Temperature-dependent regiochemical diversity in lithiation-electrophilic substitution reactions of N-BOC-2-azabicyclo[2.1.1]hexane. 2,4- and 3,5-methanoprolines.

[reaction: see text] Azabicycle 4 and sec-butyllithium/TMEDA afford the C(1) bridgehead alpha-lithio anion at 0 degrees C. Anion quenching with carbon dioxide, methyl chloroformate, or DMF provide the bridgehead acid 8a (N-BOC-2,4-methanoproline), ester 8b, or aldehyde 8c, respectively. By contrast, at -78 degrees C these same reagents give a mixture of regioisomeric methylene and bridgehead anions whose quenching leads to mixtures of regioisomeric methylene and bridgehead acids 6a/8a, esters 6b/8b, or aldehydes 6c/8c, respectively. The previously unknown 3,5-methanoproline was prepared as its N-BOC methyl ester 6b.

Anti-Bacterial Agents↗

PubMed1997

Effects of a homoanatoxin-a-containing extract from Oscillatoria formosa (Cyanophyceae/cyanobacteria) on neuromuscular transmission.

Experimental investigations were carried out with cultured and lyophilized material of the toxigenic strain Oscillatoria NIVA-CYA 92. This organism is classified as Phormidium formosum (Boryex Gom.) Anagnet kom. Aqueous extracts of the algal material, containing the bioactive secondary amine alkaloid 2-(propan-1-oxo-1-yl)-9-azabicyclo(4,2,1)non-2ene (homoanatoxin-a) in an amount of 2.57 micrograms/mg lyophilized material, were tested for acute in vivo toxicity in mice, and for toxicity on neuromuscular transmission by means of electrophysiological methods on the isolated phrenic-nerve hemidiaphragm from rat and in the frog rectus abdominis assay. Acute toxic effects in mice were observed by i.p. and oral (by gavage) administration. Lethal doses were in the range 112-225 and 1125-2250 mg of freeze-dried algal material per kg body weight (i.e. 288-578 and 2890-5780 micrograms homoanatoxin-a/ kg body weight), respectively. The nerve-initiated muscle contractions in the rat diaphragm were blocked by about 0.125 mg cyanophyte material per ml bath solution (i.e. 0.32 microgram homoanatoxin-a/ml or 1.8 microM), but muscle contractions, although slightly reduced, could still be elicited by direct electrical stimulation of the muscle. The compound action potentials recorded from the main phrenic-nerve trunk were not affected. An additive blocking effect on partly curarized preparations was observed and cholinesterase inhibition by physostigmine (eserine) transiently augmented the muscle twitch contraction in preparations partly blocked by the extract. Intracellular recordings from single muscle fibers of homoanatoxin-a-treated rat hemidiaphragm disclosed a partial depolarization and a decrease in the endplate potential to subthreshold level simultaneously with a decrease and then complete disappearance of the miniature endplate potentials. The neuromuscular transmission block was reversed by washing. The extract produced muscle contractions in the frog rectus abdominis assay. Homoanatoxin-a in the algal material was readily absorbed from the gastrointestinal tract in mice. Blockade of the neuromuscular transmission of the respiratory muscle may partly explain the acute toxic effects observed in mice. Thus, the main target of the homoanatoxin-a action at the mammalian neuromuscular junction was traced to the postsynaptic nicotinic acetylcholine receptor channel complex, where it reduced the sensitivity to the transmitter substance.

Animals↗

PubMed1987

Effect of peptidase inhibitors on [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8-induced antinociception.

The effect of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- -azabicyclo(3.3.0)octane-3-carboxylic acid (Hoe 498 diacid) and the aminopeptidase inhibitor bestatin on antinociception induced in rats by intraventricular injections of [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8 was investigated. Potentiation and prolongation of the antinociception was observed after pretreatment with bestatin. Further potentiation of the antinociception elicited by the heptapeptide was obtained in rats pretreated with a combination of bestatin and Hoe 498 diacid. In contrast, antinociception elicited by the octapeptide was not potentiated further by pretreatment with the bestatin and Hoe 498 diacid combination.

Animals↗

PubMed1996

Itasetron (DAU 6215) prevents age-related memory deficits in the rat in a multiple choice avoidance task.

The effects of itasetron (endo-N-8-methyl-8-azabicyclo-[3.2.1.]-octo-3-yl) -2,3-dihydro-2-oxo-1 H-benzimidazole-1-carboxamide hydrochloride), a 5-HT3 receptor antagonist, on discrete memory abilities of the aged rat were assessed by using the multiple choice avoidance behavioral task. Chronic treatment with itasetron (i.p., 10 micrograms/kg, b.i.d., for three consecutive weeks), but not with vehicle, significantly improved retention abilities of the aged rats in this memory test. These results further support the important role of this 5-HT3 receptor antagonist in counteracting age-related memory degeneration in rodents.

Age Factors↗

PubMed2000

Conversion of the iridoid glucoside antirrhinoside into 3-azabicyclo[3.3.0]octane building blocks.

The iridoid glucoside antirrhinoside (1) was transformed into polysubstituted 3-azabicyclo[3.3.0]octanes 3, 12, and 13 in 4 to 5 steps. Ozonolysis of the diacetonide of 1 and of its 7-deoxy-derivative 8 afforded cyclopentanoids 2 and 10, respectively. Conditions for the selective conversion of 2 and 10 into the corresponding ditosylates 4 and 11 were investigated. Cyclization of 4 and 11 was achieved with benzylamine and 2-methoxybenzylamine to yield bicyclic pyrrolidines 3, 12, and 13. Additional building blocks 14 and 15 were obtained by selective deprotection of the N-benzyl and isopropylidene moieties in 12 and 13, respectively.

Aza Compounds↗

PubMed1984

Effects of the new oral angiotensin 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) in essential hypertension.

In a dose titration study patients with mild to moderate essential hypertension were treated with increasing doses of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) (up to 8 mg daily) for 3 weeks. Hoe 498 was tolerated well. 9 out of 20 patients responded to 1 mg b.i.d., the blood pressure in a further 5 patients normalized with 2 mg b.i.d. Six patients did not respond to Hoe 498 treatment (4 mg b.i.d. in the last week) according to the criterion: recumbent diastolic blood pressure less than or equal to 90 mm Hg. But all 6 patients showed a clear decrease in blood pressure during treatment.

Adult↗

PubMed2005

Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist.

A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.

Animals↗

PubMed2001

Structure of alkaloid 275A, a novel 1-azabicyclo[5.3.0]decane from a dendrobatid frog, Dendrobates lehmanni: synthesis of the tetrahydrodiastereomers.

The principal alkaloid 275A in skins of the Colombian poison frog Dendrobates lehmanni has been identified as the pyrrolo[1,2-a]azepane (1), the first occurrence in nature of this "izidine" system. Tetrahydro-1 proved identical to one of the four synthetic diastereomers, 2a--2d, thereby establishing that 1 has the 5Z,10E relative stereochemistry. Alkaloid 1 is often accompanied by other congeners, in particular a 5Z,10Z diastereomer 15, a dihydro analogue 16, and a ketone 17. Such izidines in frogs may arise from dietary ants, as do other classes of izidines.

Alkaloids↗