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PubMed2002

Stereoselective synthesis of dipeptide beta-turn mimetics: 7-benzyl and 8-phenyl substituted azabicyclo[4.3.0]nonane amino acid esters.

A stereoselective method has been developed for the synthesis of 7- and 8-substituted dipeptide beta-turn mimetic azabicyclo[4.3.0]nonane amino acid esters. The allyl groups were introduced in high diastereoselectivity, controlled by 3-phenyl or 4-benzyl groups in pyroglutamic acid derivatives 3 or 9, respectively. The precursors, dehydroamino acids 7 and 13 derived from 5 or 11, underwent asymmetric hydrogenations with Burk's DuPHOS Rh(I)-based catalysts to furnish alpha-amino acid derivatives in high stereoselectivity. The resulting amino acids 8 and 14 were converted to the beta-turn mimetics 6,5-bicyclic lactams 1a-d in high yields.

Amino Acids↗

PubMed2004

Preparation of novel selenapenams and selenacephems by nucleophilic and radical chemistry involving benzyl selenides.

2,2a-Dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (12), 5-selena-1-azabicyclo[4.2.0]oct-3-en-8-one (13), ethyl 1-aza-7-oxo-4-selenabicyclo[3.2.0]heptane-2-carboxylate (16), and benzoselenopenem (33) can be prepared in 39-85% yield through the intramolecular homolytic substitution of aryl, vinyl or alkyl radicals at the selenium atom in suitably-substituted 4-benzylseleno-beta-lactams, or through intramolecular nucleophilic substitution by the benzylseleno moiety in 4-halo-beta-lactam precursors. Application of this chemistry to the preparation of optically active selenium-containing analogues of beta-lactam antibiotics is also detailed.

Anti-Bacterial Agents↗

PubMed1991

Inhibition of tachykinin-induced hypotension in dogs by CP-96,345, a selective blocker of NK-1 receptors.

The effects of substance P, neurokinin A, neurokinin B, [Sar9, Met(O2)11]-substance P, [Nle10]-neurokinin A (4-10) and senktide (succinyl-[Asp6, MePhe8]-substance P (6-11)) on blood pressure and heart rate were studied in anesthetized dogs. Dose-dependent decreases in blood pressure and increases in heart rate were caused by each peptide except senktide. The latter elicited weak hypotensive or hypertensive responses at high doses. The order or potency was as follows: [Sar9, Met(O2)11]-substance P greater than or equal to substance P greater than neurokinin A greater than neurokinin B greater than [Nle10]-neurokinin A (4-10) much greater than senktide. CP-96,345, [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine] a selective NK-1 tachykinin receptor blocker, inhibited substance P-induced hypotension in a dose-related manner. Responses to each of the other peptides were inhibited by CP-96,345, 1.0 mg/kg (excluding senktide against which CP-96,345 was not tested). CP-96,344 (1.0 mg/kg i.v.) the 2R-3R enantiomer of CP-96,345 which does not block NK-1 receptors, had no effect on substance P-induced hypotension. We conclude that tachykinin-induced hypotension in dogs is mediated by NK-1 tachykinin receptors.

Animals↗

PubMed2005

Scheloribatid mites as the source of pumiliotoxins in dendrobatid frogs.

The strawberry poison frog Dendrobates pumilio (Anura: Dendrobatidae) and related poison frogs contain a variety of dendrobatid alkaloids that are considered to be sequestered through the consumption of alkaloid-containing arthropods microsympatrically distributed in the habitat. In addition to ants, beetles, and millipedes, we found that adults of two species of oribatid mites belonging to the cohort Brachypylina, trophically a lower level of animal than ants and beetles, contain dendrobatid alkaloids. Gas chromatography/mass spectrometry (GC/MS) of hexane extracts of adult Scheloribates azumaensis (Oribatida: Acari) revealed the presence of not only pumiliotoxin 251D (8-hydroxy-8-methyl-6-(2'-methylhexylidene)-1-azabicyclo[4.3.0]nonane), but also precoccinelline 193C and another coccinelline-type alkaloid. From the corresponding extracts of an unidentified Scheloribates sp., pumiliotoxin 237A (8-hydroxy-8-methyl-6-(2'-methylpentylidene)-1-azabicyclo[4.3.0]nonane) was detected as a minor component, and identified by synthesis. The presence of related alkaloids, namely deoxypumiliotoxin 193H, a 6,8-diethyl-5-propenylindolizidine, and tentatively, a 1-ethyl-4-pentenynylquinolizidine, were indicated by the GC/MS fragmentation patterns, along with at least another six unidentified alkaloid components. Thus, one possible origin of pumiliotoxins, coccinellid alkaloids, and certain izidines found in poison frogs may be mites of the genus Scheloribates and perhaps related genera in the suborder Oribatida.

Alkaloids↗

PubMed2004

Conformationally constrained dipeptide surrogates with aromatic side-chains: synthesis of 4-aryl indolizidin-9-one amino acids by conjugate addition to a common alpha,omega-diaminoazelate enone intermediate.

Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.

Amination↗

PubMed1994

Dopamine D1 receptor-stimulated release of acetylcholine in rat striatum is mediated indirectly by activation of striatal neurokinin1 receptors.

Activation of dopamine D1 receptors is thought to stimulate release of striatal acetylcholine (ACh) indirectly, possibly through local release of substance P which, in turn, may enhance release of ACh. To test this hypothesis, in vivo microdialysis was used to assess the effect of neurokinin1 (NK1) receptor blockade on D1 agonist-induced increases in ACh release in the striatum of awake, freely moving rats with and without a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway. Local perfusion with the D1 agonist (+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride (SKF 38393; 1-25 microM for 20 min) increased striatal ACh release in both intact rats and rats with a 6-hydroxydopamine-induced lesion, although the increase was greater in magnitude in rats with a lesion. Local application of the NK1 antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N- [(methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345; 10 and 25 microM), but not its less active enantiomer (2R,3R)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine (CP-96,344; 10 and 25 microM), decreased the elevation in ACh induced by SKF 38393 in both intact rats and rats treated with 6-hydroxydopamine. Systemic administration of the NK1 antagonist 17-beta-hydroxy-17-a-androstanol[3.2- b]pyrimidol[1,2-a]benzimidazole hydrochloride (WIN 51,708; 20 mg/kg i.p.) also reduced the increase in ACh release induced by local perfusion of SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1999

Serotonin modulation of catalepsy induced by N(G)-nitro-L-arginine in mice.

N(G)-(Nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in mice. The objective of the present work was to investigate if serotonergic drugs are able to modulate this effect. Results showed that the cataleptogenic effect of L-NOARG (40 mg/kg) in male albino-Swiss mice was enhanced by pre-treatment with (+)-N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpro panamide ((+)-WAY-100135, 5 or 10 mg/kg), a 5-HT1A-selective receptor antagonist, and by ketanserin (5 or 10 mg/kg), a 5-HT2A receptor and alpha1-adrenoceptor antagonist. Prazosin (3 or 5 mg/kg), an alpha1-adrenoceptor antagonist, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3yl)-2,3-dihydro-3,3-dimet hyl-indole-1-carboxamide HCl (BRL-46470A, 0.05 or 0.5 mg/kg), a 5-HT3 receptor antagonist, did not interfere with L-NOARG-induced catalepsy. Ritanserin (3 or 10 mg/kg), a 5-HT2A and 5-HT2C receptor antagonist, tended to enhance the effect of L-NOARG. These results confirm that interference with the formation of nitric oxide induces catalepsy in mice, and suggest that this effect is modulated by 5-HT1A and 5-HT2A receptors.

Adrenergic alpha-Antagonists↗

PubMed2004

A straightforward and versatile synthetic approach to 1-azabicyclic alkaloids.

A very straightforward route to 1-azabicyclo alkaloid scaffolds with several ring sizes is reported. The final bicyclic structures were built through a synthetic scheme that involved (i) the construction of dienic 4-piperidone systems by an imino-Diels-Alder reaction between aminotrienes and N-omega-vinylimines, in the presence of Yb(OTf)(3), and (ii) the ring-closing metathesis reaction of these cyclic dienes, under the influence of the first-generation Grubbs' Ru-complex catalyst. During this investigations, various polysubstituted azabicyclic ring skeletons, including several examples of the quinolizidine alkaloids, are reported, and their relative stereochemistry is adequately discussed.

Alkaloids↗

PubMed2003

Synthesis and nicotinic binding studies on enantiopure pinnamine variants with an 8-azabicyclo[3.2.1]octane moiety.

Bioisosteric replacement of the 9-azabicyclo[4.2.1]nonane pharmacophoric element of the novel alkaloidal marine toxine pinnamine (5) by the 8-azabicyclo[3.2.1]octane moiety resulted in conformationally restricted analogues 6a and 6c of (-)-ferruginine (4). Key step in the diastereoselective synthesis of these pyranotropanes was the condensation of enantiopure ecgonine methyl ester (9) from the "chiral pool" with the lithium anion of N-tert-butylbutyraldimin and subsequent cyclisation with TFA. The potential nAChR ligands were tested for their in vitro affinity for the (alpha4)2(beta2)3 and the alpha7* nAChR subtypes. Despite obvious structural similarities with the potent alkaloids pinnamine (5) and (-)-ferruginine (4) the pyranotropanes 6a and 6c exhibited distinctly lower nAChR affinities.

Animals↗

PubMed2004

Substituted 2-azabicyclo[2.1.1]hexanes as constrained proline analogues: implications for collagen stability.

Among the proteinogenic amino acids, only proline is a secondary amine and only proline has a saturated ring. Electronegative substituents on C-4 (that is, C(gamma)) have a substantial effect on the trans/cis ratio of the prolyl peptide bond and the pucker of the pyrrolidine ring. 2-Azabicyclo[2.1.1]hexane is, in essence, a proline analogue with two C(gamma) atoms, one in each of the two prevalent ring puckers of proline. Here, 2-azabicyclo[2.1.1]hexane analogues of 2S-proline, (2S,4S)-4-hydroxyproline, and (2S,4S)-4-fluoroproline residues were synthesized, and their trans/cis ratios were shown to be invariant in a particular solvent. Thus, the substitution of a proline residue on C-4 affects the trans/cis ratio by altering the pucker of its pyrrolidine ring. This finding has implications for the conformation of collagen, which has an abundance of 2S-proline and (2S,4R)-4-hydroxyproline residues, and can be stabilized by (2S,4R)-4-fluoroproline and (2S,4S)-4-fluoroproline residues.

Bridged Bicyclo Compounds, Heterocyclic↗

PubMed1992

Comparison of the effects of selective and nonselective muscarinic agonists on cognition and thermoregulation in primates.

Peripheral toxicity may explain the disappointing therapeutic effects of nonselective muscarinic agonists in Alzheimer's disease. Partial agonists might exhibit an improved therapeutic index. We compare the central and peripheral cholinergic effects of RS86 with the M1/M3 partial agonists AF 102B and L-689,660 ((-)-3-[2-6 chloropyrazin)yl]-1-azabicyclo[2.2.2]octane) in primates. Administration of RS86 (1.5-2.25 mg/kg i.m.) or L-689,660 (0.1-0.3 mg/kg i.m.), but not AF 102B (up to 6 mg/kg i.m.), caused partial reversal of the disruptive effects of scopolamine on cognition. However, performance remained significantly poorer than in untreated control animals. Adverse effects prevented examination of higher doses. Centrally-mediated hypothermia was induced by RS86 (0.05 mg/kg p.o.) and L-689,660 (0.01 mg/kg p.o.) but only by a high dose of AF 102B (7 mg/kg p.o.). The putative therapeutic advantages of partial M1/M3 agonists over RS86 are discussed.

Animals↗

PubMed2004

Effects of a selective inhibitor of inducible nitric oxide synthase, ONO-1714, on experimental hemodialysis-related hypotension in renal dysfunctional dogs.

The effect of a selective inducible nitric oxide synthase inhibitor, ONO-1714 ((1S,5S,6R,7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride), on hemodialysis-related hypotension was investigated using a canine model of renal dysfunction. Renal dysfunction was induced in dogs by complete bilateral ligation of renal arteries. On performing hemodialysis with ultrafiltration, the blood pressure of the renal dysfunction dogs gradually decreased and persisted at reduced levels until completion. ONO-1714 ameliorated the hemodialysis-induced hypotension in the renal dysfunction dogs at a dose that did not influence blood pressure in non-hemodialysis dogs with normal renal function. The above findings indicated that ONO-1714 may elicit beneficial effects on hemodialysis-related hypotension.

Amidines↗

PubMed1994

Prolonged anti-emetic activity and 5-HT3-receptor antagonism by BRL 46470 in conscious ferrets.

The anti-emetic activity of oral and intravenously-administered BRL 46470 (endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3yl)-2,3-dihydro-3,3- dimethyl-indole-1-carboxamide HCl) has been assessed in conscious ferrets. BRL 46470 (0.05-0.5 mg kg-1, p.o.) dose-dependently prevented emesis evoked over a 2 h period by total body X-irradiation. This anti-emetic activity occurred with oral or intravenously-administered BRL 46470 even when dosed 3-4 h before radiation. In conjunction with data obtained in other species, we conclude that BRL 46470 has a potent and long-lasting ability to antagonize actions that are mediated by the 5-HT3 receptor in-vivo.

Administration, Oral↗

PubMed1994

A marked change of receptor affinity of the 2-methyl-5-(3-hydroxyphenyl)morphans upon attachment of an (E)-8-benzylidene moiety: synthesis and evaluation of a new class of sigma receptor ligands.

The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding enantiomers of 5 and 6 were obtained in > 99% optical purity from the optical isomers of 4, resolved with the O,O'-dibenzoyltartaric acids. The absolute configurations of the enantiomers of 4 were determined by conversion, via Clemmensen reduction, to the enantiomers of 1, the configurations of which are known. The determination of the regioisomer and configurational isomer of 5, with respect to the introduced benzylidene group, was determined from a single-crystal X-ray analysis. 1H NMR data was used to confirm that 6 possessed the same configuration as 5. Radioreceptor binding studies in rat and guinea pig brain preparations revealed that (-)-(1S,5S)-5 displayed an 11-fold decrease in affinity for the opioid mu receptor and an increase in affinity for sigma receptors of 81-fold (low nanomolar affinity) relative to the ketone precursor (+)-(1S,5S)-4. An analogous, albeit less dramatic, trend was seen with compound (-)-(1S,5S)-6. Compounds (-)-(1S,5S)-5 and (-)-(1S,5S)-6 are distinct from the typical sigma-opiates in that they have very low affinity for either PCP sites or muscarinic receptors. The high affinity and selectivity of these novel sigma receptor ligands suggests that they will be valuable for the elucidation of the functional roles of sigma receptors.

Analgesics↗

PubMed1998

Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist.

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

3T3 Cells↗

PubMed2003

Synthesis of bridged azabicyclic structures via ring-closing olefin metathesis.

A new strategy for the facile synthesis of azabicyclo[m.n.1]alkenes (m = 3-5; n = 3, 2) has been developed that involves the ring-closing metathesis (RCM) reaction of cis-2,6-dialkenyl-N-acyl piperidine derivatives. The requisite 2,6-dialkenylpiperidines may be readily prepared in six steps starting from glutarimide (11) or three steps from 4-methoxypyridine (25). In one example that establishes the practical utility of the procedure, the functionalized 8-azabicyclo[3.2.1]octane 32, which is a potential intermediate for the syntheses of various tropane alkaloids, was prepared. Additionally, a new route for the construction of the bridged tetrahydro-beta-carboline ring system 5 has been developed that features the ring-closing metathesis of the enyne 45 to construct the bridging ring in 46. This concise route to 46 also features a potentially general and useful procedure for the one-step preparation of a terminal alkyne from an ester function. Selective oxidation of the vinyl group in 46 afforded the unsaturated aldehyde 47, which may serve as a useful intermediate in syntheses of several Sarpagine alkaloids.

Alkenes↗

PubMed1989

BRL 24924: a potent agonist at a non-classical 5-HT receptor positively coupled with adenylate cyclase in colliculi neurons.

A non-classical 5-hydroxytryptamine (5-HT) receptor that we have previously proposed to call 5-HT4 and which mediates stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture was also stimulated by substituted benzamide derivatives such as metoclopramide and BRL 24924 ([ (+/-)-(endo)]-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo-[3.3.1]-non- 4-yl)-benzamide hydrochloride). The non-additivity of the effects of 5-HT and BRL 24924 on cAMP formation and the inhibition by ICS 205 930, a potent 5-HT3 antagonist, suggest that 5-HT and BRL 24924 act on the same receptor. In light of these results, we think that a similarity may exist between the non-classical 5-HT receptor, coupled with an adenylate cyclase in colliculi neurons, and the non-classical 5-HT receptor, involved in gastric and ileum motility which is specifically stimulated by substituted benzamide derivatives in the same order of potency (metoclopramide, BRL 24924).

Adenylyl Cyclases↗

PubMed1995

Antibronchospastic activity of MEN10,627, a novel tachykinin NK2 receptor antagonist, in guinea-pig airways.

The antibronchospastic activity against acetylcholine, antigen, histamine plus platelet-activating factor (PAF) or the selective tachykinin neurokinin (NK)1 and NK2 receptor agonists of the novel tachykinin NK2 receptor antagonist, MEN10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta)), was studied in anesthetized guinea-pigs. MEN10,627 (30-100 nmol/kg i.v.) reduced in a dose-dependent manner the bronchospasm induced by the tachykinin NK2 receptor agonist [beta Ala8]neurokinin A-(4-10) and the effect of the highest dose lasted up to 5 h from its administration. Conversely, airway constriction induced by the NK1 receptor agonist [Sar9]substance P sulfone or acetylcholine was unaffected by MEN10,627 up to a dose of 3 mumol/kg i.v. In animals sensitized with ovalbumin and pretreated with the endopeptidase inhibitor phosphoramidon, the aerosolized antigen produced a bronchospasm which was inhibited by MEN10,627 (30-100 nmol/kg i.v.) but not by the tachykinin NK1 receptor antagonist, (+/-)-CP96,345 ([2R,3R-cis- and [2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine]) (3 mumol/kg i.v.). Both MEN10,627 (30-100 nmol/kg i.v.) and (+/-)-CP96,345 (30-300 nmol/kg i.v.) reduced the PAF-induced hyperresponsiveness to histamine, without affecting the hypotension induced by PAF or the bronchospasm induced by histamine in guinea-pigs not exposed to PAF, showing the involvement of both tachykinin NK1 and NK2 receptors in this model. In summary, MEN10,627 behaves as a potent, selective and long-lasting tachykinin NK2 receptor antagonist in vivo. Further, tachykinin NK2 receptors could be activated during allergic responses and in the development of airway hyperresponsiveness.

Acetylcholine↗