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PubMed1998

Endothelin ET(B) receptors show different binding profiles in intact cells and cell membrane preparations.

We examined the affinity of endothelin-1, endothelin-3 and four endothelin receptor ligands, BQ788 (cis-2,6-dimethylpiperidinocarbonyl-gamma-methyl-Leu-D-Trp(1-CO 2CH3-D-Nle-ONa), SB-209670 ((+)-(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedio xyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid), IRL-1620 (succinyl-[Glu9,Ala11,15]endothelin-1(8-21)), and L-749329 (3',4'-methylenedioxy-1-(2-propyl-4-carboxyphenoxy)-N-(4-isopropyl -phenylsulfonyl)-benzene acetamide), for endothelin ET(B) receptors in human and rat heart cells. The affinities of these ligands showed good correlation between both types of living cells and between their membrane preparations (r = 0.861, P < 0.001), but less significant correlation between each of the living cells and its respective membrane preparation (r = 0.569, 0.02 < P < 0.05). These results suggest that there is no species difference in the affinities of these ligands and that destruction of the intact cell membrane structure may lead to changes in binding properties of the endothelin ET(B) receptor.

Animals↗
PubMed1999

The 5HT(1A) receptor ligand, S15535, antagonises G-protein activation: a [35S]GTPgammaS and [3H]S15535 autoradiography study.

4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine (S15535) is a highly selective ligand at 5-HT(1A) receptors. The present study compared its autoradiographic labelling of rat brain sections with its functional actions, visualised by guanylyl-5'-[gamma-thio]-triphosphate ([35S]GTPgammaS) autoradiography, which affords a measure of G-protein activation. [3H]S15535 binding was highest in hippocampus, frontal cortex, entorhinal cortex, lateral septum, interpeduncular nucleus and dorsal raphe, consistent with specific labelling of 5-HT(1A) receptors. In functional studies, S15535 (10 microM) did not markedly stimulate G-protein activation in any brain region, but abolished the activation induced by the selective 5-HT(1A) agonist, (+)-8-hydroxy-dipropyl-aminotetralin ((+)-8-OH-DPAT, 1 microM), in structures enriched in [3H]S15535 labelling. S15535 did not block 5-HT-stimulated activation in caudate nucleus or substantia nigra, regions where (+)-8-OH-DPAT was ineffective and [3H]S15535 binding was absent. Interestingly, S15535 attenuated (+)-8-OH-DPAT and 5-HT-stimulated G-protein activation in dorsal raphe, a region in which S15535 is known to exhibit agonist properties in vivo [Lejeune, F., Millan, M.J., 1998. Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)(1A) receptors: WAY100,635-reversible actions of the highly selective ligands, flesinoxan and S15535. Synapse 30, 172-180.]. The present data show that (i) [3H]S15535 labels pre- and post-synaptic populations of 5-HT(1A) sites in rat brain sections, (ii) S15535 exhibits antagonist properties at post-synaptic 5-HT(1A) receptors in corticolimbic regions, and (iii) S15535 also attenuates agonist-stimulated G-protein activation at raphe-localised 5-HT(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMedDate not supplied

Agonist and inverse agonist efficacy at human recombinant serotonin 5-HT1A receptors as a function of receptor:G-protein stoichiometry.

Membrane preparations were made from Chinese Hamster Ovary (CHO) cells expressing 1.6 and 4.2 pmol/mg of recombinant human 5-HT1A receptors, as determined by saturation binding with the selective antagonist, [3H]-S 15535 ([3H]-4-(benzodioxan-5-yl)]-(indan-2-yl)piperazine). There was no change in the number of G-proteins activated by the full agonist, serotonin (5-HT; approximately 1.1 pmol/mg in each preparation, measured by [35S]-GTP gamma S saturation binding), therefore increasing the receptor:G-protein ratio from approximately 1.4:1 (RGlow) to approximately 4:1 (RGhigh). Agonist efficacy was measured by stimulation of [35S]-GTP gamma S binding. The serotonergic agonist, eltoprazine, behaved as a partial agonist (Emax = 52.7%) at RGlow membranes but virtually as a full agonist (Emax = 93.2%) at RGhigh membranes, relative to 5-HT (= 100%). The latter exhibited a two-fold shift to the left in its concentration-response curve in RGhigh compared to RGlow membranes (P < 0.01). WAY 100,635 (N-¿2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl¿-N-(2-pyridinyl) -cyclo-hexane-carboxamide), did not alter [35S]-GTP gamma S binding from basal levels in either membrane preparation. In contrast, spiperone displayed inverse agonist activity, decreasing [35S]-GTP gamma S binding from basal levels by 17% in RGlow membranes but by 28% in RGhigh membranes. These data indicate that an increased receptor:G-protein ratio (i) augments the potency of full agonists, (ii) increases the efficacy of partial agonists and (iii) increases the negative efficacy of inverse agonists at recombinant human 5-HT1A receptors. Furthermore, these data suggest that spiperone induces, or stabilises, a G-protein-coupled, but inactive conformation of the receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Roles of 5-HT(1A) receptors in the dorsal raphe and dorsal hippocampus in anxiety assessed by the behavioral effects of 8-OH-DPAT and S 15535 in a modified Geller-Seifter conflict model.

8-OH-DPAT [8-hydroxy-2-(di-N-propylamino)tetralin], a 5-HT(1A) receptor agonist, and S 15535 (4-benzodioxan-5-yl)1-(indan-2-yl)piperazine, a partial agonist at 5-HT(1A) receptors, were administered into the dorsal raphe nucleus and dorsal hippocampus and their behavioral effects were assessed in a modified Geller-Seifter conflict model. Injected into the dorsal raphe nucleus 8-OH-DPAT, 1 microg but not 0.04 or 0.2 microg 0.5 microl(-1), and S 15535, 2.5 microg but not 0.1 or 0.5 microg 0.5 microl(-1), significantly increased punished responding with no effect on rates of unpunished or time-out responding. WAY 100635, a selective 5-HT(1A) receptor antagonist, injected subcutaneously at 0. 3 mg kg(-1) 30 min before 1 microg 8-OH-DPAT or 2.5 microg S 15535 in the dorsal raphe, completely antagonized their effects on punished responding. At doses ranging from 1 to 10 microg microl(-1) injected into the CA1 region of the dorsal hippocampus neither 8-OH-DPAT nor S 15535 modified punished responding or the rates of time-out. At the highest doses, 8-OH-DPAT significantly reduced unpunished responding whereas S 15535 had the opposite effect. The results suggest that stimulation of 5-HT(1A) receptors in the dorsal raphe nucleus has anxiolytic-like effects whereas stimulation of postsynaptic receptors in the dorsal hippocampus has no anxiolytic or anxiogenic effects, at least judging from changes in rates of punished responding. These results are compatible with the hypothesis that 5-HT(1A) receptor agonists and partial agonists attenuate anxiety by reducing serotonergic transmission in brain areas innervated by the dorsal raphe nucleus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

Syntheses of stable isotope-labeled 6 beta-hydroxycortisol, 6 beta-hydroxycortisone, and 6 beta-hydroxytestosterone.

A method is described for the preparation of two types of multi-labeled 6 beta-hydroxycortisol containing either five deuterium atoms at C-19 methyl and C-1 methylene or four 13C atoms at C-1, C-2, C-4, and C-19 in addition to the five deuterium atoms for use as analytical internal standards for gas chromatography-mass spectrometry (GC-MS). BMD derivatives of [1,1,19,19,19-2H(5)]cortisone and [1,2,4,19-13C(4),1,1,19,19,19-2H(5)]cortisone (cortisone-2H(5)-BMD and cortisone-13C(4),2H(5)-BMD) were first synthesized via indan synthon method starting from optical active 11-oxoindanylpropionic acid and labeled isopropenyl anion ([1,1,3,3,3-2H(5)]- or [1,3-13C(2),1,1,3,3,3-2H(5)]isopropenyl anion). The labeled isopropenyl anion was prepared from commercially available [1,1,1,3,3,3-2H(6)]- or [1,3-13C(2),1,1,1,3,3,3-2H(6)]acetone. Ultraviolet (UV) irradiated autoxidation at C-6 position of 3-ethyl-3,5-dienol ether derivatives of the labeled cortisone-BMDs gave 6 beta-hydroxy-[1,1,19,19,19-2H(5)]cortisone-BMD and 6 beta-hydroxy-[1,2,4,19-13C(4),1,1,19,19,19-2H(5)]cortisone-BMD, respectively, as a mixture of 6 beta- and 6 alpha-epimers in a ratio of 4:1. Separation of 6 beta- and 6 alpha-epimers by thin-layer chromatography (TLC) and subsequent hydrolysis of the BMD group at C-17 gave pure labeled 6 beta-hydroxycortisone. After protecting the keto group at C-3 of the labeled 6 beta-hydroxycortisone-BMD as semicarbazone, reduction of 11-keto group with NaBH(4) and subsequent removal of the C-3 and C-17 protecting groups gave 6beta-hydroxy-[1,1,19,19,19-2H(5)]cortisol (6 beta-hydroxycortisol-2H(5)) and 6 beta-hydroxy-[1,2,4,19-13C(4),1,1,19,19,19-2H(5)]cortisol (6 beta-hydroxycortisol-13C(4),2H(5)), respectively, as a mixture of 6 beta- and 6 alpha-epimers (6 beta:6 alpha=4.4:1). The isotopic compositions of 6 beta-hydroxycortisol-2H(5) and 6 beta-hydroxycortisol-13C(4),2H(5) were 90.9 and 92.1 at.%, respectively. Furthermore, 6 beta-hydroxy-[1 alpha,16,16,17 alpha-2H(4)]testosterone was synthesized by the UV irradiated autoxidation at C-6 position of 3-ethyl-3,5-dienol ether derivative of deuterium-labeled testosterone ([1 alpha,16,16,17 alpha-2H(4)]testosterone) obtained by using catalytic deuteration and hydrogen-deuterium exchange reactions.

Carbon Isotopes↗
PubMed2000

Synthesis of multi-labeled cortisols and cortisones with (2)H and (13)C for study of cortisol metabolism in humans.

A method is described for the preparation of multi-labeled cortisol and cortisone with (13)C and (2)H via the indan synthon method, starting from chiral 11-oxoindanylpropionic acid. [1, 3-(13)C(2)]Acetone was used for the syntheses of [1,2,4, 19-(13)C(4)]cortisol (cortisol-(13)C(4)) and [1,2,4, 19-(13)C(4)]cortisone (cortisone-(13)C(4)), and [1,3-(13)C(2),1,1,1, 3,3,3-(2)H(6)]acetone was for [1,2,4,19-(13)C(4),1,1,19,19, 19-(2)H(5)]cortisol (cortisol-(13)C(4),(2)H(5)) and [1,2,4, 19-(13)C(4),1,1,19,19,19-(2)H(5)]cortisone (cortisone-(13)C(4), (2)H(5)). The chemical shifts for the (13)C and (1)H NMR spectra of cortisol and cortisone were fully assigned.

Carbon Isotopes↗
PubMed2002

Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)(1B) receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT(1B) receptors and has been employed for characterization of cerebral 5-HT(1B) receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT(1B) sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t(1/2)=3.4 min), >90% specific binding and high affinity (K(d)=0.6 nM) for a homogeneous population of receptors with a density (B(max)) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT(1B) agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pK(i), 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (minus sign)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291; <5.0). Similarly, affinities were established for 13 chemically diverse antagonists, including N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125,743; pK(i), 9.1), (-)cyanopindolol (9.0), (-)-tertatolol (8.2), N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl)biphenyl-4-carboxamide (GR127,935; 8.2), N-[3-(1,4-benzodioxan-5-yl)piperidin-4-yl]N-(indan-2yl)amine (S18127; 7.9), metergoline (7.8), (-)-pindolol (7.6), 1'-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] (SB224,289; 7.5) and ketanserin (<5.0). These rank orders of affinity correspond to the binding profile of 5-HT(1B) rather than 5-HT(1D) receptors. The low affinities of L775,066 and PNU109,291 versus L694,247 should be noted, as well as the low affinity of ketanserin as compared to SB224,289. Finally, in line with species differences, the affinities of several ligands including CP93,129, RU24,969, (-)-pindolol and (-)-propanolol in rat 5-HT(1B) sites were markedly different to guinea pig 5-HT(1B) sites labelled with [3H]GR125,743. In conclusion, [3H]GR125,743 is an appropriate tool for the radiolabelling of native, rat 5-HT(1B) receptors and permitted determination of the affinities of an extensive series of ligands at these sites.

Animals↗
PubMed1998

NPY Y1 antagonists: structure-activity relationships of arginine derivatives and hybrid compounds with arpromidine-like partial structures.

Previously, omega-guanidino- and omega-aminoalkanamides, structurally derived from arpromidine-like histamine H2 receptor agonists, were reported as novel neuropeptide Y Y1 antagonists. Regardless of the backbone, they resemble BIBP 3226, an argininamide with high NPY Y1 receptor affinity and selectivity, with respect to nature and arrangement of the 'terminal' diaryl, guanidine, and hydroxyphenyl groups. Hybrid compounds were synthesized combining the argininamide backbone of BIBP 3226 or partial structures derived from the C-terminal dipeptide of NPY with characteristic substructures of arpromidine- or amide-type NPY antagonists. Additionally, some analogs of BIBP 3226 with reduced flexibility were prepared. Structure-activity relationships indicate that, in contrast to alkanamides, homologs and/or isomers of BIBP 3226 with vicinal arrangement of the phenyl rings have decreased Y1 antagonistic activity (Ca2+-assay in HEL cells). Replacement of the hydroxybenzyl group by an imidazole ring further decreases activity. It is concluded that the binding sites of NPY antagonists with one and with two basic groups are not identical. Analogs with a rigid tetrahydro-2-benzazepine or an indan group in place of the benzyl moiety in BIBP 3226 are active, indicating the role of the OH group and supporting the model proposed for the interaction of BIBP 3226 with the Y1 receptor.

Arginine↗
PubMed2001

Aromatase inhibitors: past, present and future.

For the cellular physiology of sex steroid sensitive cells, the androgen/estrogen ratio may be more important than only one hormone action per se, in both sexes. This ratio is controlled in vertebrates by aromatase; its gene expression can be inhibited in different ways, and this is crucial for the treatment of estrogen-dependent diseases such as breast cancer, or gynecomastia in males for instance. To reach this goal, new steroidal and non-steroidal inhibitors are continuously being developed, and some of them are used as first or second line agents. Aromatase inhibition is also an essential tool for studying the role of estrogens in the adult, or during development. Aromatase inhibitors have shown in particular that estrogens are essential also in males for skeletal maturation and bone mineralization, development of masculine dendritic morphology in male brain linked to mating behaviour, and testicular function. Testosterone is often the prohormone converted in situ in active estrogens, at these levels. Several strategies can be used for aromatase inhibition. The first ones employed were blind screening or deductions from in vivo observations, which led for instance to the discovery of the role of aminoglutethimide in aromatase inhibition. Subsequently, in the years 1975-1990, the molecular modeling of compounds to mimic the substrate shape of the enzyme constituted the major idea. Hundreds of chemicals were synthesized by numerous authors, ranging from the well-known and very efficient 4-OHA to complicated imidazole or indane derivatives tested by sophisticated comparative molecular field analyses. Reticulum-bound active aromatase has not as yet been X-ray analyzed. Thus, aromatase inhibitors were also used more recently to probe and understand the active site conformation of the enzyme and its modelization was obtained from comparisons with bacterial-related cytochromes. We developed a mammalian model considerably closer to human aromatase in order to study the active site shape with new potent aromatase non-steroidal inhibitors. This model is equine aromatase. This enzyme was biochemically characterized, purified, and cloned by our group. It allowed testing, by site-directed mutagenesis, predictive hypotheses in human aromatase which contributed to designing of new inhibitors. The understanding of the functioning of an essential member of the cytochrome P450 family, which is necessary for cellular detoxification, was also facilitated. Inhibition of aromatase activity has also been carried out with antibodies directed to the catalytic site and at the gene level by knock-out or by control of factor-specific promoters. This may result in different mRNA synthesized by alternative splicing. We have also obtained specific inhibition of aromatase activity in human cells with antisense stable phosphorothioate oligodeoxynucleotides directed against aromatase mRNA tertiary structures. Besides known steroidal and non-steroidal inhibitors, the antiaromatase effects of compounds found in our daily environment such as dietary flavonoids or xenobiotic pollutants have also been described. Finally, we underline that all these aromatase inhibitors, or methods of aromatase inhibition, can modulate the estrogenic balance essential not only for female, but also for male physiology, including gonadal function.

Animals↗
PubMed1999

Polycyclic musk fragrances in the aquatic environment.

The polycyclic musk fragrances, mainly 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta(g)-2-ben zopyrane (HHCB) and 7-acetyl-1,1,3,4,4,6-hexamethyltetrahydronaphthalene (AHTN) are synthetic musk fragrances which are used in almost all scented consumer products, such as perfumes, cosmetics and laundry detergents. Concerning their chemical structures the polycyclic musks are indane and tetraline derivatives highly substituted mainly by methyl groups. Their production has been increased continuously during the last years with a world-wide production volume today of about 6000 t/year. After their application in private households they are dumped via the sewage treatment plants into the aquatic environment. In this review the analysis of polycyclic musk compounds in environmental samples is shortly presented and all published data of polycyclic musk compounds in water, sediment, suspended particulate matter (SPM), sewage sludge, and biota are summarized and discussed. The highest HHCB and AHTN concentrations were analysed in water (maximum concentrations: 6 microg HHCB/l, 4.4 microg AHTN/1) and sludge (maximum concentrations: 63 mg HHCB/kg dry matter, 34 mg AHTN/kg dry matter) from sewage plants, and in fish (maximum concentrations: 159 mg HHCB/kg lipid, 58 mg AHTN/kg lipid) from sewage ponds. In all other samples from different aquatic ecosystems these chemicals were unequivocally detected in varying concentrations dependent on the distance to sewage treatment plants. Even in marine water samples from the German Bight HHCB and AHTN could be quantified at the lower ng/l level. Very often HHCB and AHTN formed the major organic contaminants, in all samples their concentrations exceeded those of musk xylene and musk ketone. Also several by-products and impurities of the commercial polycyclic musks were analysed in river and waste water samples in not negligible amounts. The apparently ubiquitous distribution of polycyclic musks in the aquatic environment demonstrates the persistence and lipophilicity of these pollutants. The high log K(ow) values of HHCB and AHTN (5.7-5.9) do not directly correlate with their relatively low bioconcentration factors (BCFs) derived from fish experiments, this discrepancy may be explained by a particular metabolism in fish. There are indications of a possible species dependent metabolisation. For a general risk assessment of this new group of environmental pollutants besides the missing toxicological data, further studies on the distribution of the polycyclic musk fragrances including their by-products in the aquatic environment, on possible degradation processes in sediment/sludge as well as on the metabolism in fish are urgently needed.

Animals↗
PubMedDate not supplied

MR 20492 and MR 20494: two indolizinone derivatives that strongly inhibit human aromatase.

In this study, we describe the synthesis of a new family of indolizinone derivatives designed to fit an extrahydrophobic pocket within the active site of aromatase and to strongly inhibit human aromatase. This could help improve the specificity of the inhibitors. Equine aromatase, very well characterized biochemically, is used as a comparative model. Indeed, in a previous comparison between both human and equine aromatases, we described the importance of the interaction between the inhibitor and this pocket for the indane derivative MR 20814. MR 20492 and MR 20494 are more potent inhibitors of human aromatase (Ki/Km: 1.0+/-0.3 and 0.5+/-0.3, respectively). The Ki/Km for MR 20494 is slightly higher than that obtained for fadrozole (0.1+/-0.0) and Ki/Km for both indolizinone derivatives are lower than those obtained for 4-hydroxyandrostenedione (1.9+/-0.8) and MR 20814 (8.1+/-.7). These new compounds are not enzyme inactivators. Moreover, as indicated by the higher Ki/Km values obtained with equine enzyme (9.0+/-0.6 and 6.1+/-1.6 for MR 20492 and MR 20494, respectively), both human and equine aromatase active sites appear to be structurally different. Difference absorption spectra study (350-500 nm) revealed that MR20492 and MR20494 were characterized by a combination of type-I and -II spectra with both enzymes. This result could be due to the isomerization of the molecule in polar solvent (Z and E forms). The evaluation of these new molecules, as well as 4-hydroxyandrostenedione and fadrozole, on aromatase activity in transfected 293 cell cultures evidenced a strong inhibition (IC50: 0.20+/-0.03 microM, 0.20+/-0.02 microM and 0.50+/-0.40 microM for MR 20494, fadrozole and 4-OHA, respectively) except for MR 20492 (3.9+/-0.9 microM) and MR 20814 (10.5+/-0.6 microM). These results proved that these molecules formed part of a promising family of potent inhibitors and that they penetrate 293 cells, without evidencing any cytotoxicity in Hela cells with MTT assay. This is thus encouraging for the development of new drugs for the treatment of estrogen-dependent cancers, these molecules also constitute new tools for understanding the aromatase active site.

Animals↗
PubMed1998

Potent 3-spiropiperidine growth hormone secretagogues.

Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the growth hormone secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford secretagogues with low nanomolar in vitro activity.

Animals↗
PubMed2002

9-Carboxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-2-carbocylic acid (RPR117824): selective anticonvulsive and neuroprotective AMPA antagonist.

Excessive release of glutamate, a potent excitatory neurotransmitter, is thought to play an important role in a variety of acute and chronic neurological disorders, suggesting that excitatory amino acid antagonists may have broad therapeutic potential in neurology. Here, we describe the synthesis, pharmacological properties and neuroprotective activity of 9-carboxymethyl-imidazo-[1-2a]indeno[1-2e]pyrazin-4-one-2-carboxylic acid (RPR117824), an original selective AMPA antagonist. RPR117824 can be obtained through a six-step synthesis starting from (1-oxo-indan-4-yl) acetic acid, which has been validated on a gram-scale with an overall yield of 25%. Monosodium or disodium salts of the compound exhibit excellent solubility in saline (> or = 10 g/L), enabling intravenous administration. RPR117824 displays nanomolar affinity (IC(50)=18 nM) for AMPA receptors and competitive inhibition of electrophysiological responses mediated by AMPA receptors heterologously expressed in Xenopus oocytes (K(B)=5 nM) and native receptors in rat brain slices (IC(50)=0.36 microM). In in vivo testing, RPR117824 behaves as a powerful blocker of convulsions induced in mice or rats by supramaximal electroshock or chemoconvulsive agents such as pentylenetetrazole, bicuculline, isoniazide, strychnine, 4-aminopyridine and harmaline with half maximal effective doses ranging from 1.5 to 10 mg/kg following subcutaneous or intraperitoneal administration. In disease models in rats and gerbils, RPR117824 possesses significant neuroprotective activity in global and focal cerebral ischemia, and brain and spinal cord trauma.

Animals↗
PubMed2002

Synthesis of constrained phenylalanine derivatives via a [2+2+2] cycloaddition strategy.

A simple synthesis of dialkyne building blocks (6, 7, 8 and 9) embodying amino acid moiety is described. The dialkyne 6 participated in a [2+2+2] cycloaddition reaction with various monoalkynes in presence of Wilkinson's catalyst to give 5- and 5,6-disubstituted indan-based -amino acid derivatives. Cobalt catalyst [e.g., CpCo(CO)2] has also been employed in the synthesis of various 2-indanyl glycine derivatives via co-trimerization reaction of the diyne building blocks 6 and 7 with several monoalkynes.

Cobalt↗
PubMed2002

6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.

Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model.

Animals↗
PubMed2001

Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A.

The asymmetric total synthesis of both enantiomers of the potent antitumor antibiotic fredericamycin A (1) is detailed based on the protocol for the construction of its peri-hydroxy polyaromatic skeleton bearing the chirality at the spiro carbon via a strong base-induced cycloaddition of suitably substituted homophthalic anhydrides (AB-ring unit) with an optically active CDEF-ring unit. Particular attention has been given to the novel synthesis of the optically active spiro carbon center by a stereospecific rearrangement of optically active benzofuzed-trans-epoxy acylates leading to spirocyclopentane-1,1'-indane systems. This method is quite useful for the construction of an optically active spiro compound and was applied to the synthesis of the optically pure CDEF-ring unit of 1. Cycloaddition of the optically pure CDEF-ring unit to AB-ring units prepared via benzyne afforded two natural and unnatural-type hexacyclic compounds, which were converted to natural and unnatural enantiomers of synthetic 1, and the absolute configuration of natural 1 was determined as S.

Antibiotics, Antineoplastic↗
PubMed2001

Carbomethoxychlorocarbene: spectroscopy, theory, chemistry and kinetics.

Photolysis (254 nm) of methyl 8-chloro-3a,7a-methanoindan-8-carboxylate (5) in argon at 14 K produces carbomethoxychlorocarbene (6) as a persistent species. The IR and UV-vis spectra of the carbene were recorded and analyzed with the aid of density functional calculations (B3-LYP/6-31G). The IR spectrum of 6 is consistent with the carbene having a nonplanar singlet ground state, in agreement with the G3(MP2)//B3-LYP calculations of Scott and Radom (accompanying paper). Irradiation (300 nm) of 5 in solution produces indane in 97% yield. In cyclohexane, carbene 6 is trapped by insertion into a CH bond, whereas in 2,3-dimethylbutene it adds to the double bond to form a cyclopropane. Laser flash photolysis of 5 (308 nm, 17 ns, XeCl excimer) produces carbene 6 which reacts with pyridine to form an ylide (lambda(max) = 440 nm). It was possible to resolve the growth of the ylide in Freon-113 (CF(2)ClCFCl(2)) to measure the lifetime (tau = 114 ns, ambient temperature) of the carbene and the absolute rate constant of its reaction with pyridine (k(pyr) = 2 x 10(9) M(-)(1) s(-)(1)). A plot of log(1/tau) versus 1/T in CF(2)ClCFCl(2) is linear with Arrhenius parameters E(a) = 10.9 +/- 0.8 kJ/mol and A = 10(9.1)(+/-)(0.2) s(-)(1). In perfluorohexane, a less reactive solvent than Freon-113, E(a) = 23.4 +/- 1.7 kJ/mol, A = 10(10.6)(+/-)(0.) s(-)(1), and tau = 354 ns at 293 K. It is argued that the activation barrier to carbene disappearance in perfluorohexane represents the lower limit to the barrier to Wolff rearrangement of the carbene.

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PubMed2003

Generation and characterization of highly strained dibenzotetrakisdehydro[12]annulene.

We report here the generation of tetrakisdehydro[12]annulene possessing a highly deformed triyne component from the [4.3.2]propellatriene-annelated precursor by its photolysis extruding indan and the characterization of the highly reactive annulene by chemical and spectroscopic methods. In addition to the chemical evidence for the formation of the title compound in solution such as interception as a Diels-Alder adduct, we succeeded in its characterization by UV-vis and FTIR spectra in an argon matrix at 20 K. The experimental IR spectrum agreed well with the theoretical one calculated by the DFT method.

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