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PubMed2005

7,8-Dihydroxy-4-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolinium bromide monohydrate, a dopamine agonist.

In the crystal structure of the title dopaminergic compound, C16H24NO2+.Br-.H2O, protonation occurs at the piperidine N atom. The piperidine ring adopts a chair conformation and the cyclohexene ring adopts a half-chair conformation; together with the planar benzene ring, this results in a relatively planar shape for the whole molecule. Classical hydrogen bonds (N-H...Br, O-H...Br and O-H...O) produce an infinite three-dimensional network. Hydrogen bonds between water molecules and Br- anions create centrosymmetric rings throughout the crystal structure. Structural comparison of the molecule with the ergoline dopamine agonist pergolide shows that it is the hydrogen-bond-forming hydroxy or imino group that is necessary for dopaminergic activity, rather than the presence of a phenyl or a pyrrole ring per se.

Crystallography, X-Ray↗
PubMed2005

Formation of quinol co-crystals with hydrogen-bond acceptors.

The crystal structures of eight new co-crystals of quinol with pyrazine, piperazine, morpholine, pyridine, piperidine, 4,4'-bipyridine, N-methylmorpholine and N,N'-dimethylpiperazine are reported. Quinol forms 1:1 co-crystals with pyrazine, piperazine and N,N'-dimethylpiperazine, but 1:2 co-crystals with morpholine, 4,4'-bipyridine, N-methylmorpholine, pyridine and piperidine. This difference can be rationalized in most cases by the presence of, respectively, two or one strong hydrogen-bond acceptor(s) in the guest molecule. The exception to this generalization is 4,4'-bipyridine, which forms a 1:2 co-crystal, possibly to optimize crystal packing. All structures are dominated by hydrogen bonding between quinol and the guest molecules. A doubly bridging motif, which connects pairs of quinol and guest molecules via NH...O or CH...O interactions, is present in all but the sterically hindered N,N'-dimethylpiperazine and N-methylmorpholine co-crystals.

Crystallization↗
PubMed1980

Solid-phase peptide synthesis of somatostatin using mild base cleavage of N alpha-9-fluorenylmethyloxycarbonylamino acids.

Experimental details for the "Fmoc solid phase peptide synthesis" of somatostatin are described. The 9-fluorenylmethyloxycarbonyl group was rapidly and quantitatively cleaved by 55% piperidine in dimethylformamide and monitored (u.v.) manually. For a kinetic study, a centrifugal reactor with a photometric control system and reference cell was used at each stage. The symmetrical anhydride coupling reaction was rapid and either acetic anhydride or fluorescamine termination was incorporated to minimize formation of deletion peptides. Anchor-bond cleavage was effected with trifluoroacetic acid which simultaneously removed all the acid labile tert.-butyl side chain protecting groups. N alpha-9-fluorenylmethyloxycarbonyl peptides may be obtained by omitting the piperidine deprotection step after the last cycle of synthesis. From several syntheses, analytically pure di-S-protected somatostatin 14-peptide was obtained in 55-60% overall yield. The S-protecting groups were removed and the product was purified by gel filtration to give homogeneous dihydrosomatostatin (91%) yield. Oxidation of dihydrosomatostatin with potassium ferricyanide and purification by countercurrent distribution provided analytically pure homogeneous somatostatin.

Amino Acid Sequence↗
PubMed1990

Solution phase synthesis of Saccharomyces cerevisiae a-mating factor and its analogs.

The solution phase synthesis of the Saccharomyces cerevisiae a-mating factor and nonfarnesylated and nonmethylated a-factor analogs are reported. The a-factor, a lipopeptide with the sequence Tyr-Ile-Ile-Lys-Gly-Val-Phe-Trp-Asp-Pro-Ala-Cys(S-Farnesyl)OCH3 was synthesized by the condensation of the amine terminal protected decapeptide with the carboxyl terminal farnesylated dipeptide using benzotriazol-l-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent) as the coupling agent. The synthesis of the decapeptide involved 5 + 5 fragment coupling with the BOP reagent and the successful application of 9-fluorenylmethyl ester(OFm) and 9-fluorenylmethoxycarbonyl(Fmoc) groups for the protection of Asp and Lys side chains and Tyr alpha-amine and of phenacyl esters (OPa) for alpha-carboxyl protection. The OFm and Fmoc groups tolerated repeated couplings and were completely stable to zinc powder in acetic acid, a condition under which the OPa group was removed. The synthesis of the nonfarnesylated alpha-factor was accomplished by the coupling of the decapeptide with tetrapeptide (Ala-CysOCH3)2 followed by the deprotection of the OFm and Fmoc groups with piperidine and the cleavage of the disulfide bond with zinc powder in acetic acid. The nonmethylated a-factor was prepared by 10 + 2 fragment coupling using OFm protection of the dipeptide carboxyl group followed by removal of all protecting groups with piperidine. Attempts to saponify a-factor were not successful. The synthetic nonfarnesylated and nonmethylated a-mating pheromones were 100-1000 times less active than the a-factor, indicating that although the methyl ester and the farnesyl group are not essential for biological activity, they are necessary for high potency.

Amino Acid Sequence↗
PubMed1996

Lipoconjugates: structure-activity studies for pheromone analogues of Ustilago maydis with varied lipophilicity.

The synthesis, biological activities and conformational behaviour of a variety of analogues of the mating pheromones of the basidomycete Ustilago maydis are reported. The pheromone analogues derived from the two allelic forms H-G-R-D-N-G-S-P-I-G-Y-S-S-Xaa-Z (a1) and H-N-R-G-Q-P-G-Y-Y-Xaa-Z (a2), with Xaa-Z being an unidentified lipophilic cysteine derivative, all differ in the C-terminal residue and include -Cys(farnesyl)-OMe, -Cys(farnesyl)-OH, -Cys(prenyl)-OMe, -Cys-OMe, -Cys(n-dodecyl)-OMe and the unnatural residues -Ahds-OMe (Ahds=alpha-aminohexadecanoic acid), -Ahds-OH, -Ads-OMe (Ads=alpha-aminodecanoic acid) and -N-Hdg-OMe (N-Hdg=N-hexadecylglycine). The synthesis of the unnatural methyl ester analogues was carried out by condensation of the fully protected fragments Fmoc-G-R(Pmc)-D(tBu)-N(Trt)-G-S(tBu)-P-I-G-Y(tBu)-S(tBu)-S(tBu)-OH (a1') and Fmoc-N(Trt)-R(Pmc)-G-Q(Trt)-P-G-Y(tBu)-Y(tBu)-OH (a2') respectively, prepared by Fmoc-SPPS, with the appropriate methylester compounds and subsequent deprotection with TFA/scavenger and piperidine. Synthesis and physicochemical properties of the unnatural lipophilic amino acid methylesters are described. The preparation of the cysteine analogues was performed by condensation of a1' or a2' with H-Cys(Trt)-OMe and subsequent deprotection with TFA/scavenger. Alkylation of the thiol function and Fmoc-deprotection was achieved in a novel one-pot reaction by treatment with alkyl bromide and DIPEA, quenching with EDT and Fmoc removal by addition of 20% piperidine (v/v). Hydrolysis of the methyl esters was carried out by treatment with NaOH in MeOH/H2O. The results of the biological assay reveal an increase in activity with increasing chain length of the lipophilic anchor, with alkyl being better than prenyl and sulfur being not essential, while the position of the anchor is optimal at C7 and the methyl ester moiety is important. NMR studies of two chosen analogues in DMSO and SDS/water demonstrate that the lipophilic C-terminal residue has no influence on the structural behaviour of the peptides. Chemical-shift and NOE patterns indicate a main all-trans conformation of the peptide backbone and a weakly populated cis conformation around the Xaa Pro peptide bond in all eight cases without formation of a defined folded structure. No evidence is seen that the membrane-simulating system SDS/water has a structure-inducing effect on the bound peptide. We therefore conclude that the lipomodification in mating pheromones of U. maydis acts to increase the effective concentration of the drug in the target cell membrane without additional structure-inducing or receptor-binding effects.

Alkylation↗
PubMed1990

Properties of purified squalene-hopene cyclase from Bacillus acidocaldarius.

The squalene-hopene cyclase from Bacillus acidocaldarius cytoplasmic membrane, was purified to homogeneity by solubilization with Triton X-100, chromatography on DEAE-cellulose, phenyl Sepharose and two gel-filtration columns. The enzyme monomer had a molecular mass of 75 kDa. The sequence of the first 23 amino acids was determined by Edman degradation. The enzyme activity was efficiently inhibited by n-alkyldimethylammonium halides with alkyl chain lengths between 12 and 18 C atoms. Inhibition was also observed with (5-hydroxycarvacryl)trimethylammonium chloride 1-piperidine carboxylate, dodecyldimethylamine N-oxide, azasqualene and farnesol. Competitive inhibition with dodecyltrimethylammonium bromide, (5-hydroxycarvacryl)trimethylammonium chloride 1-piperidine carboxylate and dodecyldimethylamine N-oxide was demonstrated by Lineweaver-Burk plots.

Amino Acid Sequence↗
PubMed1980

L-Pipecolate formation in the mammalian brain. Regional distribution of delta1-pyrroline-2-carboxylate reductase activity.

L-Pipecolate formation exhibits considerable regional differences in the central nervous system of the mouse, dog, and monkey, as reflected in measurements of the activity of delta1-pyrroline-2-carboxylate reductase (D.C. 1.5.1.1). The rate of reduction of delta1-piperidine-2-carboxylate was high in certain telencephalic and diencephalic regions, lower in the brain stem, and not measurable in the cerebellum and spinal cord. In addition to delta1-piperidine-2-carboxylate, delta1-pyrroline-2-carboxylate was also found to be a substrate for the same enzyme in homogenates of mouse forebrain. Enzyme kinetic data for both substrates and, in addition, for NADH were derived from determinations using enzyme fractions of mouse telencephalon. The discussion is based on earlier findings concerning the utilisation of D-proline in the neuronal protein synthesis of mouse brain.

Animals↗
PubMed1990

Pharmacological characteristics and distributions of sigma- and phencyclidine receptors in the animal kingdom.

The phylogenetic distributions of sigma- and phencyclidine receptors in neural tissues of 13 species and the pharmacological characteristics of these receptors in whole sea anemone and neural tissues of the guinea pig, chicken, and frog were studied. Specific binding of [3H]haloperidol and [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine, ligands that bind with high affinity to sigma- and phencyclidine receptors, respectively, was detected in all organisms examined. The order of potencies of various ligands to inhibit 1 nM [3H]haloperidol binding in brains of frogs and guinea pigs or 1 nM [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine in chicken or guinea pig brain homogenates was very similar. However, the characteristics and stereospecificity of binding of the two radioligands in sea anemone were different than in higher organisms. The results suggest that sigma- and phencyclidine binding sites are evolutionarily old, as the characteristics of the two sites are well preserved over a range of vertebrate phyla.

Animals↗
PubMed1992

Binding properties of 3-[125I]iodophencyclidine, a new radioligand for N-methyl-D-aspartate-gated ionic channels.

The binding properties of the 125I-labeled phencyclidine derivative N-[1-(3-[125I]iodophenyl)cyclohexyl]piperidine (3-[125I]iodo-PCP), a new ligand of the N-methyl-D-aspartate (NMDA)-gated ionic channel, were investigated. Association and dissociation kinetic curves of 3-[125I]iodo-PCP with rat brain homogenates were well described by two components. About 32% of the binding was of fast association and fast dissociation, and the remaining binding was of slow association and slow dissociation. Saturation curves of 3-[125I]iodo-PCP also were well described using two binding sites: one of a high affinity (KDH = 15.8 +/- 2.3 nM) and the other of a low affinity (KDL = 250 +/- 40 nM). 3-Iodo-PCP inhibited the binding of 3-[125I]iodo-PCP with inhibition curves that were well fitted by a two-site model. The binding constants (KiH, BmaxH; KiL, BmaxL) so obtained were close to those obtained in saturation experiments. Ligands of NMDA-gated ionic channels also inhibited the binding of 3-[125I]iodo-PCP with two constants, KiH and KiL. There was a very good correlation (r = 0.987) between the affinities of these ligands to bind to NMDA-gated ionic channels and their potencies to inhibit the binding of 3-[125I]iodo-PCP with a high affinity. Moreover, the regional distribution of the high-affinity binding of 3-[125I]-iodo-PCP paralleled that of tritiated N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP). In contrast to that of [3H] TCP, the binding of 3-[125I]iodo-PCP to well-washed rat brain membranes was fast and insensitive to glutamate and glycine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

The effects of cyclic dicarboxylic acids on spontaneous and amino acid-evoked activity of rat cortical neurones.

1 A series of cyclic dicarboxylic acids were applied by microiontophoresis to neurones in the cerebral cortex of rats anaesthetized with urethane. The object was to examine effects on spontaneous firing rates and any ability to antagonize responses to excitatory amino acids. 2 At relatively low ejecting currents (10-25 nA) cis-2,3-piperidine dicarboxylic acid (cis-2,3-PDA) had no effect on spontaneous firing but selectively antagonized the excitation evoked by n-methyl-D-aspartate (NMDA) without affecting responses to quisqualaife or kainate. At higher ejecting currents (60-100 nA) responses to all three agonists were reduced. 3 Other cis-piperidine dicarboxylic acids and piperazine-2,3-dicarboxylic acid had only weak and variable effects on cell firing and responses to NMDA, quisqualate, kainate, glutamate and aspartate. 4 2, 3-Pyridine dicarboxylic acid (quinolinic acid) produced excitation of all cortical neurones tested. 5 2-Amino-5-phosphono-valeric acid, an NMDA antagonist, reduced responses to quinolinate, implying that this compound can act at NMDA receptors. 6 It is suggested that quinolinic acid may be of physiological interest as a potential endogenous excitant in the nervous system and that cis-2,3-PDA and its N-methyl derivative may be of use in studies of receptor pharmacology and the identification of synaptic transmitters.

Amino Acids↗
PubMed1988

A comparison between the in vivo and in vitro activity of five potent and competitive NMDA antagonists.

1. Phosphonate analogues of glutamate have been tested and compared as N-methyl-D-aspartate (NMDA) antagonists in electrophysiological and binding experiments. The compounds tested were three established NMDA antagonists: D-2-amino-5-phosphonopentanoate (D-AP5), DL-2-amino-7-phosphonoheptanoate (DL-AP7), 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), and two novel putative NMDA antagonists: 3-(2-carboxypiperidin-4-yl)propyl-1-phosphonate (CPPP) and 3-(2-carboxy-piperidin-4-yl)methyl-1-phosphonate (CPMP). 2. When administered electrophoretically to rat spinal neurones in vivo, these compounds were found to be selective NMDA antagonists with little effect on excitations evoked by quisqualate and kainate. CPMP and CPPP were approximately equipotent with CPP and about 5 times more potent than D-AP5. 3. Following systemic administration, 2-5 mg kg-1 i.v. of CPP, CPMP and CPPP reduced NMDA-evoked excitations by 70-100% whereas 50-100 mg kg-1 of D-AP5 and DL-AP7 produced a similar effect. The onset of the effects required 20-30 min and lasted more than six hours. 4. On bath application to cortical wedges, the IC50 values (microM) for antagonism of 40 microM NMDA were: CPP, 0.64 +/- 0.06 (mean +/- s.e.mean; n greater than 4); CPMP, 1.65 +/- 0.13; CPPP 0.89 +/- 0.09; D-AP5, 3.7 +/- 0.32; DL-AP7, 11.1 +/- 2.1; and DL-AP4 and DL-AP6 were inactive at 100 microM. 5. In binding studies with [3H]-CPP, the Ki values (nM) were: CPP, 446 + 150 (mean + s.e.mean; n > 3); CPMP, 183 + 74 and CPPP, 179 +/- 13 whereas against NMDA (lO microM)-stimulated [3H]- TCP (thienylcyclohexylpiperidine) binding the ICjo values (microM) for CPMP and CPPP respectively were 5.6 + 2.7 and 4.5 + 2.2. 6. Systemic administration of CPPP and CPMP, at doses sufficient to antagonize NMDA, also reduced cardiovascular responses to 5-hydroxytryptamine (Bezold-Jarisch reflex). This illustrates a role for NMDA receptors in central cardiovascular control. 7. The results indicate the systemic doses of piperidine and piperazine analogues of D-AP5 which may be used for assessing the role ofNMDA receptors in central synaptic function.

2-Amino-5-phosphonovalerate↗
PubMed1996

Functional interactions between muscarinic M2 receptors and 5-hydroxytryptamine (5-HT)4 receptors and beta 3-adrenoceptors in isolated oesophageal muscularis mucosae of the rat.

1. Relaxations of isolated oesophageal muscularis mucosae of rat are mediated by 5-hydroxytryptamine (5-HT), acting at 5-HT4 receptors, and isoprenaline, principally acting via beta 3-adrenoceptors. The aim of this study was to investigate the hypothesis that muscarinic M2 receptors, also present in this tissue, functionally oppose 5-HT and beta-adrenoceptor-relaxant effects in this preparation. 2. Contractions of rat oesophageal muscularis mucosae were induced, in a concentration-dependent manner, by the muscarinic receptor agonist, oxotremorine M (pEC50 = 6.7 +/- 0.1). The contractile responses to oxotremorine M were surmountably antagonized by the following compounds, (pKB values in parentheses): atropine (9.1 +/- 0.2), 4-DAMP (4-diphenylacetoxy-N-methyl piperidine methiodide, 8.7 +/- 0.1), p-F-HHSiD (para-fluoro-hexa-hydro-siladifenidol, 7.5 +/- 0.1), zamifenacin (8.6 +/- 0.3), himbacine (7.2 +/- 0.2), pirenzepine (6.8 +/- 0.3) and methoctramine (6.2 +/- 0.2). These data are consistent with a role for muscarinic M3 receptors mediating contractions to oxotremorine M. The contractile response was associated with a low receptor reserve, since the responses were shifted to the right and virtually abolished by the alkylating agent, 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl) piperidine, 40 nM; 60 min equilibration). 3. In tissues precontracted with U46619 (0.7 microM; approx. EC90), isoprenaline (pEC50 = 8.0 +/- 0.1) and 5-HT (pEC50 = 7.5 +/- 0.2) induced concentration-dependent relaxations. The isoprenaline potency was slightly, but significantly, different in tissues precontracted with oxotremorine M (isoprenaline, pEC50 = 7.4 +/- 0.2). In contrast, the potency of 5-HT (pEC50 = 7.5 +/- 0.2), in tissues that were precontracted with 1 microM (EC90) oxotremorine M, was identical. When these experiments were repeated in the presence of the muscarinic M2 receptor antagonist, methoctramine (1 microM), there was no effect on the relaxant potencies to either 5-HT or isoprenaline. Collectively, these data suggest that muscarinic M2 receptors do not, under these conditions, modulate relaxant potencies to either 5-HT or isoprenaline. 4. In a second protocol, tissues were pre-contracted with U46619 (0.7 microM) and relaxed with either 5-HT (0.1 microM) or isoprenaline (0.1 microM). In these tissues (in which the muscarinic M3 receptor population was extensively depleted by alkylation), oxotremorine M caused concentration-dependent re-contractions (i.e. reversal of relaxations). In tissues relaxed with 5-HT, the potency of oxtremorine M was 5.9 +/- 0.2, while in tissues relaxed with isoprenaline, the potency (pEC50) = 5.6 +/- 0.3. These re-contractions were antagonized, in a surmountable fashion, by methoctramine (1 microM; pKB = 7.6 +/- 0.1). Similar observations were seen when relaxations were induced by isoprenaline (1 microM; pKB = 7.5 +/- 0.2). Under these conditions, therefore, the pKB values are consistent with activation of muscarinic M2 receptors, and inconsistent with activation of M3 receptors. 5. It is concluded that in isolated oesophageal muscularis mucosae of rat, muscarinic M3 receptors mediate direct contractions and are associated with a low receptor reserve. When this population is depleted, and the tissues relaxed via activation of receptors that augment adenylyl cyclase activity, a functional role for muscarinic M2 receptors is revealed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Analysis of viral DNA, protein and envelope damage after methylene blue, phthalocyanine derivative or merocyanine 540 photosensitization.

Although numerous photosensitizers have been used experimentally to decontaminate viruses in cellular blood components, little is known about their mechanisms of photoinactivation. Using M13 bacteriophage and vesicular stomatitis virus (VSV) as model viruses, we have investigated alteration of the viral genome, protein and envelope after phototreatment. Methylene blue (MB) and aluminum phthalocyanine tetrasulfonate (AlPcS4) phototreatment inactivated bacteriophage M13 and decreased the fraction of single-stranded circular genomic DNA (sc-DNA) by converting it to linear form. This conversion was enhanced by treating the extracted DNA with piperidine at 55 degrees C. Piperidine-labile breaks were well correlated to phage survival (5.1% sc-DNA at 1.7% phage survival for MB) under conditions where only minor differences were seen in the relative abundance of M13 coat protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Neither aluminum phthalocyanine (AlPc) nor merocyanine 540 (MC540) inactivated M13 nor were there significant changes observed in DNA and coat protein. Methylene blue, AlPcS4 and AlPc inactivated VSV and inhibited fusion of the virus envelope to Vero cells at pH 5.7 (i.e. with plasma membrane). However, the degree of this inhibition was small compared to the extent of virus inactivation (43% inhibition vs. 4.7 log10 or 99.998% inactivation, for MB). In contrast, an antibody to VSV G-spike protein inhibited fusion at pH 5.7 by 52% with a concomitant decline in VSV infectivity of 0.15 log10 (30%). Few changes were observed in the relative abundance of G protein for MB and AlPcS4 phototreated samples and no additional protein bands were observed on SDS-PAGE.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

N-methyl-D-aspartate-activated channels of mouse central neurones in magnesium-free solutions.

1. The whole-cell and outside-out configurations of the patch-clamp method were used to investigate the properties of the channels activated by N-methyl-D-aspartate (NMDA channels) in mouse central neurones in culture. Recording was made in Mg2+-free solutions. 2. In the whole-cell recording mode the currents induced by both NMDA and L-glutamate were accompanied by a large increase in noise. In both cases the noise power spectra were well fitted by single Lorentzian functions and the corresponding mean time constant, tau, was about 6 ms at room temperature. The single-channel conductance, gamma n, estimated from the ratio of the noise variance to the total current, varied between 22 and 40 pS. 3. Endogenous amino acids known to activate NMDA receptors (L-glutamate, L-aspartate, L-cysteine sulphinate and quinolinate) as well as exogenous NMDA agonists such as ibotenate and trans-2,3-piperidine dicarboxylate (trans-PDA) all produced similar responses. In particular, analysis of the current noise yielded tau values between 4 and 8 ms in all cases. 4. NMDA responses were antagonized by 2-amino-5-phosphonovalerate (APV) without any effect on gamma n or tau values measured by noise analysis; NMDA responses were also diminished by D-alpha-aminoadipate and cis-2,3-piperidine dicarboxylate. 5. In outside-out patches, it was observed that the single-channel current amplitude varies linearly as a function of membrane potential between -80 and +60 mV. The reversal potential is near 0 mV. NMDA channels are permeable to Na+, K+ and Cs+, but blocked by choline. The single-channel conductance, gamma e, varies between 40 and 50 pS at room temperature. 6. The NMDA channels open in bursts of short openings interrupted by brief closures. At -60 mV, the closures had a mean duration, tc, of 0.4 +/- 0.2 ms. The mean channel open time, to, was 5.9 +/- 1.0 ms for NMDA and 5.3 +/- 1.7 ms for L-glutamate. The mean burst duration, tb, was 10.5 +/- 0.7 ms for NMDA and 8.5 +/- 2.0 ms for L-glutamate. 7. When the temperature was increased between 14 and 24 degrees C, the NMDA channel conductance increased with a Q10 of 1.6 while the mean open time decreased with a Q10 close to 2. 8. The NMDA channel showed, in addition to the 'main' conductance state (40-50 pS), smaller conductance states of 15 and 35 pS.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2002

Identification of metabolites of a substance P (neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma.

[3R,5R,6S]-3-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane is a substance P (Neurokinin 1 receptor) antagonist. Substance P antagonists are proven in concept to have excellent potential for the treatment of major depression, and they allow superior and sustained protection from acute and delayed chemotherapy-induced emesis. The metabolism of this compound was investigated in rat hepatocytes, and circulating rat plasma metabolites were identified following oral and intravenous dosing. The turnover in rat hepatocytes within 4 h was about 30%, and the major metabolites were identified as two nitrones and a lactam associated with the piperidine ring. Although these metabolites were also observed in rat plasma, the major circulating metabolite was a keto acid following oxidative de-amination of the piperidine ring. Liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance were used to confirm the structure of the latter metabolite. A mechanism leading to the formation of the keto acid metabolite has been suggested, and most intermediates were observed in rat plasma.

Administration, Oral↗
PubMed2003

Steroids modulate N-methyl-D-aspartate-stimulated [3H] dopamine release from rat striatum via sigma receptors.

Steroids have been proposed as endogenous ligands at sigma receptors. In the current study, we examined the ability of steroids to regulate N-methyl-d-aspartate (NMDA)-stimulated [3H]dopamine release from slices of rat striatal tissue. We found that both progesterone and pregnenolone inhibit [3H]dopamine release in a concentration-dependent manner similarly to prototypical agonists, such as (+)-pentazocine. The inhibition seen by both progesterone and pregnenolone exhibits IC50 values consistent with reported Ki values for these steroids obtained in binding studies, and was fully reversed by both the sigma1 antagonist 1-(cyclopropylmethyl)-4-2'-4"flurophenyl)-2'oxoethyl)piperidine HBr (DuP734) and the sigma2 antagonist 1'-[4-[1-(4-fluorophenyl)-1-H-indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H), 4'piperidine] (Lu28-179). Lastly, to determine whether a protein kinase C (PKC) signaling system might be involved in the inhibition of NMDA-stimulated [3H]dopamine release, we tested the PKCbeta-selective inhibitor 5,21:12,17-dimetheno-18H-dibenzo[i,o]pyrrolo[3,4 - 1][1,8]diacyclohexadecine-18,20(19H)-dione,8-[(dimethylamino)methyl]-6,7,8,9,10,11-hexahydro-monomethanesulfonate (9Cl) (LY379196) against both progesterone and pregnenolone. We found that LY379196 at 30 nM reversed the inhibition of release by both progesterone and pregnenolone. These findings support steroids as candidates for endogenous ligands at sigma receptors.

Animals↗
PubMed2003

Ca2+ responses in Chinese hamster ovary-K1 cells demonstrate an atypical pattern of ligand-induced 5-HT1A receptor activation.

Little experimental evidence has been reported for diverse signaling via 5-hydroxytryptamine (5-HT)1A receptors despite the fact that agonists seem to be more efficacious at dorsal raphe somatodendritic 5-HT1A autoreceptors than at postsynaptic 5-HT1A receptors. The present study investigated Ca2+ responses in Chinese hamster ovary (CHO)-K1 cells expressing a human 5-HT1A receptor by 5-HT, prototypical 5-HT1A agonists, N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methyl-6-; methylaminopyridin-2-yl)-methylaminomethyl]-piperidine (F 14679), and especially N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-; methylaminomethyl]piperidine (F 13640) as representative ligands of a new chemical class (methylamino-pyridine) that combines both high efficacy and selectivity for 5-HT1A receptors. 5-HT (pEC50 = 6.70 +/- 0.02) induced a pertussis toxin-sensitive, transient high-magnitude Ca2+ response. High-magnitude Ca2+ responses (Emax, percentage versus 5-HT) were also found with F 13640 (107 +/- 4), 5-carboxamidotryptamine (100 +/- 3), and F 14679 (87 +/- 3). In contrast, the prototypical 5-HT1A receptor agonists buspirone, ipsapirone, and 8-(hydroxy-2-(di-n-propylamino)tetralin, and also flesinoxan and eptapirone, were virtually inactive (< or =5). This atypical pattern of 5-HT1A receptor activation contrasts with the broad spectrum of the ligands' partial agonist properties as observed by measuring guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding responses with membranes of either CHO-K1 or C6-glial cells stably expressing a human 5-HT1A receptor. Remarkably, differences between ligands that seem small in the [35S]GTPgammaS binding assay translate into huge differences in the magnitude of Ca2+ responses. Therefore, some of these 5-HT1A ligands (i.e., F 13640) may in a selective way induce responses that may be not at all be achieved with other ligands (i.e., buspirone). In conclusion, the pharmacology of 5-HT1A receptor ligands seems to be codetermined by the effector pathway.

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

Antithrombotic effects of FK419, a novel nonpeptide platelet GPIIb/IIIa antagonist, in a guinea pig photochemically induced middle cerebral artery thrombosis model: comparison with ozagrel and argatroban.

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

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