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PubMed2002

Synthesis and nicotinic binding studies on enantiopure diazine analogues of the novel (2-chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene UB-165.

As part of our program aimed at optimizing therapeutic effects over toxic effects (as observed in the naturally occurring nicotinic acetylcholine receptor modulators (-)-nicotine, (-)-epibatidine, (-)-ferruginine, and (+)-anatoxin-a), we investigated the bioisosteric potential of diazines in the field of (+)-anatoxin-a-type structures. In the series of diazine analogues of deschloro-UB-165 (DUB-165, 6), bioisosteric replacement of the 3-pyridyl pharmacophoric element by a 4-pyridazinyl, 5-pyrimidinyl, or 2-pyrazinyl moiety resulted in novel nAChR ligands 7, 8, and 9. A palladium-catalyzed Suzuki cross-coupling of the 3-diethylboranylpyridine (14) and a Stille cross-coupling of the corresponding tributylstannyl diazines 15-17 with the vinyl triflate 13 of the N-protected 9-azabicyclo[4.2.1]nonan-2-one 12 constitute the key steps in the syntheses of these enantiopure anatoxinoids 6-9. Studies of the in vitro affinity for (alpha4)(2)(beta2)(3), alpha3(beta)4, and alpha7 nAChR subtypes by radioligand binding assays demonstrated that the diazine analogues 7-9 can be considered as pharmacologically attractive bioisosteres of DUB-165 (6) but with different effects on the binding affinity with regard to the diazine moiety. The pyrimidine-containing bioisostere 8 turned out to be the most active diazine analogue, which interacts potently (K(i) = 0.14 nM) with the (alpha4)(2)(beta2)(3) subtype and differentiates significantly among the nAChR subtypes investigated. The nitrogens in this anatoxinoid 8 show by far the most negative atomic charges (calculated using the AM1 Hamiltonian). This qualitatively correlates with the highest binding affinity observed for 8 for all subtypes under consideration.

Adrenal Glands↗

PubMed2003

Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury.

Previously, we have shown that primary afferent sensory neurons are necessary for disease activity in T cell-mediated immune hepatitis in mice. In the present study, we analyzed the possible role of substance P (SP), an important proinflammatory neuropeptide of these nerve fibers, in an in vivo mouse model of liver inflammation. Liver injury was induced by bacterial lipopolysaccharide (LPS) in D-galactosamine (GalN)-sensitized mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment down-regulated circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) and protected mice from GalN/LPS-induced liver injury. Likewise, pretreatment of mice with antagonists of the SP-specific neurokinin-1 receptor (NK-1R), i.e., (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060), dose dependently protected mice from GalN/LPS-induced liver injury. The presence of the NK-1R in the murine liver was demonstrated by reverse transcription-polymerase chain reaction, sequence analysis, and immunocytochemistry. NK-1R blockade reduced inflammatory liver damage, i.e., edema formation, neutrophil infiltration, hepatocyte apoptosis, and necrosis. To get further insight into the mechanism by which receptor blockade attenuated GalN/LPS-induced liver damage, we analyzed plasma levels and intrahepatic expression of TNFalpha, IFNgamma, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFalpha and IFNgamma, whereas synthesis of the hepatoprotective cytokines IL-6 and IL-10 was increased. NK-1 receptor antagonists might be potent drugs for treatment of inflammatory liver disease, most likely by inhibiting SP effects.

Animals↗

PubMed2001

The inducible nitric oxide synthase inhibitor ONO-1714 blunts dextran sulfate sodium colitis in mice.

In mice with acute dextran sulfate sodium colitis, we examined the effect of inducible nitric oxide synthase inhibition by (1S,5S,6R,7R)-7chloro-3-amino-5methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714) on colonic biochemistry, injury, and inflammation. Colonic luminal nitrate and nitrite were measured by the Griess reaction; inducible nitric oxide synthase messenger RNA expression by reverse transcription-polymerase chain reaction; and nitrotyrosine by immunohistochemistry. Mice with colitis showed increases in nitrate and nitrite, inducible nitric oxide synthase messenger RNA, and numbers of cells staining for nitrotyrosine. Colonic inflammation was severe. ONO-1714 inhibited increases in nitrate and nitrite and numbers of nitrotyrosine-positive cells; injury and inflammation also were reduced. Dextran sulfate sodium-induced increases in thiobarbituric acid-reactive substances, a lipid peroxidation marker, were blunted by ONO-1714, which also inhibited increases in mucosal inflammatory cytokines. Nitric oxide produced by inducible nitric oxide synthase may contribute to colonic inflammation by nitrosation, oxidative damage, and enhanced inflammatory cytokines.

Amidines↗

PubMed1997

[125I]IPH, an epibatidine analog, binds with high affinity to neuronal nicotinic cholinergic receptors.

An analog of epibatidine (EB) was synthesized with an iodine atom in the 2 position of the pyridyl ring. This analog, (+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), as well as its two stereoisomers, displayed high affinity for neuronal nicotinic receptors; therefore, radioiodinated IPH, [125I]IPH, was synthesized with specific radioactivities consistently > 1000 Ci/mmol, and its properties as a radioligand for neuronal nicotinic receptors were evaluated. The characteristics of [125I]IPH binding in tissue homogenates appeared to be virtually identical to those reported for [3H]epibatidine binding; but the high specific radioactivity of [125I]IPH greatly facilitated measurements of nicotinic receptors in tissues with relatively low receptor densities and/or where tissues are in limited supply. Autoradiography with [125I]IPH provided clear localization of nicotinic receptors in brain and adrenal gland after film exposure times of < or = 2 days. We conclude that [125I]IPH will be a very useful radioligand for the study of neuronal nicotinic receptors in brain and in peripheral ganglia.

Animals↗

PubMed1985

A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid A new class of A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid pumiliotoxin B (8-hydroxy-8-methyl-6-alkylidene-1-azabicyclo[4.3.0]nonanes).

Pumiliotoxin B (PTX-B, 6-(6',7'-dihydroxy-2',5'-dimethyl-(E)-4'-octenylidene)-8-hydroxy-8 -methyl-1- azabicyclo-[4.3.0] nonane) increases the force of contractures of spontaneously beating guinea pig atrial strips by 3- to 5-fold with half-maximal effects at about 3 microM and increases rates of atrial contractions by 2- to 3-fold with half-maximal effects at about 6 microM. The presence of an axial 7-hydroxy substituent (PTX 339A) decreases the efficacy but not the potency of PTX-B as a positive inotropic agent while having only slight effects on activity as a positive chronotropic agent. The presence of an equatorial 7-hydroxy substituent (PTX 339B) greatly decreases efficacy and potency of PTX-B as a positive chronotropic and inotropic agent. Pumiliotoxin A which lacks the side-chain 7'-hydroxy group of PTX-B causes only a 2-fold increase in force of contracture at 54 microM while having minimal effects on rate. The presence of an axial 7-hydroxy substituent (PTX 323B' and 323B", epimeric at the 6'-hydroxy) markedly enhances positive inotropic and chronotropic effects of PTX-A. Another congener, PTX 251D with a 6-(2'-methylhexylidene) side chain, and a synthetic analogue with a 6-(6'-heptenylidene) side chain are cardiac depressants. Both lack hydroxyl groups in the side chain. The presence of an omega-1 hydroxy group in the side chain of PTX 251D yields an alkaloid (267C) with weak positive inotropic effects and minimal chronotropic effects. The presence of an axial 7-hydroxy group in the indolizidine ring of PTX 251D results in a compound (PTX 267A) with very weak positive inotropic effects while retaining the negative chronotropic effects of PTX 251D. A synthetic analogue with a 6-(7'-hydroxyheptylidene) side chain is a cardiac depressant even though it contains a side-chain hydroxyl corresponding in position to the 7'-hydroxyl of the side chain of PTX-B. The positive chronotropic and inotropic effects of pumiliotoxin B are reversed only by relatively high concentrations of the calcium channel blockers nifedipine and verapamil, suggesting that pumiliotoxin B may owe its cardiotonic activities to effects on internal mobilization of calcium.

Alkaloids↗

PubMed1992

Synthesis and in vitro biological profile of all four isomers of the potent muscarinic agonist 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane.

The four stereoisomers of the muscarinic agonist 7 have been synthesized from enantiomerically pure exo-azanorbornane esters (13a,b). The esters were obtained in optically active form by separation of the carboxamide diastereomers 12a,b, formed from the borane complex of exo-azanorbornane-3-carboxylate 10 and a chiral amine auxiliary. Using the known chirality of (R)-alpha-methylbenzylamine, an X-ray analysis was accomplished on 12a in order to determine the absolute configuration of the azanorbornane C4 chiral center. Each of the chiral esters 13a,b was separately transformed into the oxadiazoles with concomitant epimerization at C3 of the azanorbornane ring to afford the thermodynamic equilibrium mixture of isomers. Chromatographic separation followed by analysis of each isomer by NMR and GC allowed the absolute stereochemistry of all four isomers of 7 to be confirmed. Full biological evaluation in biochemical and pharmacological assays revealed that the 3R,4R isomer was the most active on receptor binding studies and the most potent on the pharmacological preparations, showing a 50-fold increase in potency at the M2 and M3 sites compared to M1.

Animals↗

PubMed2002

PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor.

5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha 7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha 7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha 7 receptor ligands.

Animals↗

PubMed1996

Response heterogeneity of 5-HT3 receptor antagonists in a rat visceral hypersensitivity model.

Subcutaneous administration of granisetron (BRL 43694, endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl-1 H-indazole-3-carboxamide) and zacopride (4-amino-N-(1-azabicyclo[2.2.2.]oct-3-yl)-5-chloro-2-methoxybenzamide), two 5-HT3 receptor antagonists, at doses ranging from 3 to 1000 micrograms/kg, inhibited abdominal contractions induced by distension (30 mmHg, 10 min) of irritated colon (0.6% acetic acid) in conscious rats with a bell-shaped dose-response curve. The ED50 of granisetron and zacopride were 17.6 and 8.2 micrograms/kg, respectively. In contrast, both tropisetron (ICS 205-930, (3-a-tropanyl)t-indole-3-carboxylic ester) and ondansetron (GR38032F, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)methyl]-4 H-carbazol-4-one hydrocloride dihydrate) were inactive in this model. These data further support the concept of a heterogeneity in the potency of 5-HT3 receptor antagonists in modulating visceral hypersensitivity in conscious rats. This finding is in agreement with a reported efficacy of granisetron but not of ondansetron in patients with irritable bowel syndrome.

Animals↗

PubMed2003

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.

5-Hydroxytryptophan↗

PubMedDate not supplied

BIMU1 increases associative memory in rats by activating 5-HT4 receptors.

Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo -1 H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 agonist/5-HT3 antagonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluro-2-methoxy-1H-indole-3- carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antagonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (> 15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory.

Animals↗

PubMed1998

Muscarinic agonists exhibit functional dopamine antagonism in unilaterally 6-OHDA lesioned rats.

(5R,6R) 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]oc tane (PTAC) is a selective muscarinic ligand with high affinity for central muscarinic receptors, agonist mode of action at the muscarinic M2 and M4 receptor subtypes and substantially less or no affinity for central dopamine receptors. In the present study PTAC, as well as the muscarinic agonists oxotremorine, RS86 and pilocarpine, inhibited dopamine D1 and D2 receptor agonist induced contralateral rotation in unilaterally 6-OHDA lesioned rats. The dose of SKF 38393 used to induce contralateral rotation also caused an intense Fos protein immunoreactivity in the rat dorsolateral striatum on the lesioned site which was inhibited by PTAC indicating that the inhibition of rotation by PTAC was not due to non-specific peripheral side effects.

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

PubMed2004

A tachykinin NK1 receptor antagonist attenuates the 4 beta-phorbol-12-myristate-13-acetate-induced nociceptive behaviour in the rat.

Antinociceptive effect of a tachykinin NK1 receptor antagonist ezlopitant [(2S,3S-cis)-2-(diphenylmethyl)-N-{(2-methoxy, 5-isopropylphenyl)methyl}-1-azabicyclo[2.2.2]octan-3-amine] was investigated in the 4beta-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive test in the rat. Intraplantar injection of PMA-induced paw-licking and flinching behaviour lasted up to 120 min and was accompanied by inflammatory reactions, such as swelling and invasion of granulocytes. Pretreatment with resiniferatoxin [200 microg/kg, subcutaneous (s.c.)] blocked the PMA-induced nociceptive behaviour, suggesting that vanilloid VR1 receptor-expressing primary sensory neurons play a major role in this response. Subcutaneous pretreatment with ezlopitant (0.3-30 mg/kg) and morphine (0.3-6 mg/kg) caused a dose-dependent inhibition of the behaviour. Ezlopitant (3-30 mg/kg) given subcutaneously after PMA injection also significantly attenuated the behavioural response. When administered intrathecally, ezlopitant and a nonselective glutamate receptor antagonist MK-801 had an inhibitory effect, whereas CJ-12,191, an inactive isomer of ezlopitant, was unaffected. These results suggest that spinal tachykinin NK1 receptors contribute to processing of ongoing pain associated with peripheral inflammation.

Analgesics↗

PubMedDate not supplied

Synthesis and electrophysiological studies of a novel epibatidine analogue.

The new epibatidine analogue exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (2PABH) was synthesised. Separation of enantiomers was performed on chiral HPLC chromatography in polar-organic phase mode at 0 degree C. Enantiomeric purity was greater than 99.8%ee for the (-)- and 90.5%ee for the (+)-enantiomer respectively. Optical rotation was determined to be [alpha]23D = +/- 13 degrees. Electrophysiological studies of 2PABH were carried out on alpha 4 beta 2, alpha 3 beta 4 and alpha 7 nAChR subtypes cloned from rat and reconstituted in Xenopus oocytes. Both enantiomers could not significantly activate the heteromeric subtypes. The homomeric alpha 7 nAChR displays a high sensitivity only towards (-)-2PABH. The EC50 for (-)-2PABH and ACh were determined (32.5 +/- 9.5 microM, 137.3 +/- 16.5 microM). (-)-2PABH was shown to be a partial agonist (80% of ACh). Thus the efficacy of 2PABH differs markedly from that of epibatidine. The intramolecular N-N-distance and the spatial pyridine nitrogen orientation play a central role in nAChR recognition.

Animals↗

PubMed1999

Uptake and distribution of a new SSRI, NS2381, studied by PET in living porcine brain.

This study tests the utility of a new selective serotonin reuptake inhibitor (SSRI), [11C]NS2381 {(+/-)-(8-[11C]methyl-3-(4-trifluoromethyl-phenyl)-8-azabicyclo[3.2.1]oc t-2-ene)}, as positron-emitting radioligand for labelling serotonin (5-HT) reuptake sites in living brain. Studies of monoamine uptake were carried out initially in vitro using rat brain synaptosomes. They showed that NS2381 and its precursor NS2435 are selective inhibitors of serotonin (5-HT) uptake. Then, studies were carried out in vivo on the uptake and distribution of [11C]NS2381 in living porcine brain. They showed that the radiotracer accumulates readily in brain, and binds reversibly in regions rich in serotonin uptake sites (e.g. raphe, basal ganglia and thalamus). In addition, [11C]NS2381 was displaced from brain tissue by the potent SSRI citalopram. The enantiomers of [11C]NS2381 were, in general, found to be similar to the racemate in terms of their uptake and distribution in living pig brain. Thus, [11C]NS2381 fulfilled several criteria of a PET radioligand for studying 5-HT uptake sites in the living brain.

Animals↗

PubMed1999

The GABA(B) receptor antagonist CGP36742 improves learned helplessness in rats.

Effects of 3-aminopropyl-n-butyl-phosphinic acid (CGP36742), a GABA(B) receptor antagonist, in the learned helplessness paradigm were examined in rats in comparison with those of imipramine and endo-8-methyl-8-azabicyclo[3,2,1]oct-3-ol indol-3-yl-carboxylate hydrochloride (ICS205-930). Rats were treated with CGP36742, imipramine or ICS205-930 for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks increased escape failures in the escape test. CGP36742, imipramine and ICS205-930 dose-dependently improved the escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of CGP36742, imipramine and ICS205-930. Although the action of imipramine and ICS205-930 was attenuated by 1-(m-chlorophenyl)-biguanide (mCPBG), mCPBG failed to influence the CGP36742 action. Therefore, it is suggested that CGP36742 may have an antidepressant profile and that the mechanisms of CGP36742 in antidepressant action may be different from those of imipramine and ICS205-930.

Analysis of Variance↗

PubMed2003

Efficient synthesis of enantiopure pyrrolizidinone amino acid.

Enantiopure (3S,5R,8S)-3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylic acid (1) was synthesized in nine steps and 16% overall yield from aspartate beta-aldehyde 7. Carbene-catalyzed acyloin condensation of 7, followed by acetylation and samarium iodide reduction, gave linear precursor (2S,7S)-alpha,omega-diamino-4-oxosuberate 11, which was converted to N-(Boc)aminopyrrolizidin-2-one carboxylic acid 1 by a reductive amination/lactam cyclization sequence. X-ray analysis of (3S,5R,8S)-methyl N-(Boc)aminopyrrolizidin-2-one carboxylate 21 showed that its internal backbone dihedral angles (psi = -149 degrees, phi = -49 degrees ) were in good agreement with the ideal values for a type II' beta-turn. Proton NMR experiments on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamide 23 demonstrated significantly different NH chemical displacements and temperature coefficients suggestive of solvent shielded and exposed hydrogens indicative of a turn conformation. Because pyrrolizidinone amino acids can serve as conformationally rigid dipeptide surrogates, this synthesis should facilitate their application in the exploration of conformation-activity relationships of various biologically active peptides.

Aspartic Acid↗

PubMed1985

A radioimmunoassay for the angiotensin converting enzyme inhibitor ramipril and its active metabolite.

A radioimmunoassay (RIA) has been developed for the measurement of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)- 2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril, Hoe 498) and its active metabolite (diacid: hydrolysis product of ramipril) in serum or plasma. Antibodies to the diacid were raised in rabbits against a lysine analogue conjugated to bovine serum albumin. A 125I-ramipril-diacid derivative was used as radioligand. Separation of the antibody-bound and free radiolabeled ligand was achieved by employing a polyethylene glycol solution. The RIA is specific for the active metabolite (diacid). Studies on specificity showed less than 0.6% cross-reactivity with intact ramipril or with dioxopiperazine metabolites. The levels for intact ramipril were obtained by prior enzymatic hydrolysis to the diacid. The sensitivity of the assay was 0.1 and 0.5 ng/ml for diacid and ramipril, respectively. Intra- and inter-assay coefficients of variation ranged from 3 to 14% at 1 to 30 ng diacid per ml. A recovery experiment yielded an average of 103%. The assay has been used to investigate the pharmacokinetic profile of both ramipril and its pharmacologically active metabolite.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1992

Homoanatoxin: a potent analogue of anatoxin-A.

The natural toxin anatoxin-a (AnTx) is a potent nicotinic agonist that is valuable for the study of nicotinic receptors. We have synthesized 2-(propan-1-oxo-1-yl)-9-azabicyclo[4.2.1]non-2-ene, the homologue of AnTx in which the side-chain is extended by one methylene unit from a methyl to an ethyl ketone. This chemistry would allow the generation of a tritiated product and the homologue, designated homoanatoxin (HomoAnTx), has been characterized here with that aim in mind. In competition binding assays at neuronal nicotinic ligand binding sites characterized by [3H]nicotine and [125I]-alpha bungarotoxin, HomoAnTx retained the same potency as the parent molecule, with Ki values of 7.5 nM and 1.1 microM, respectively. In contrast, it showed little inhibition of muscarinic binding defined by [3H]-quinuclidinyl benzilate. HomoAnTx is a potent nicotinic agonist in frog muscle contracture assays, having four times the potency of carbamylcholine and one tenth of the activity of AnTx itself. The N-methylated version of HomoAnTx was more than two orders of magnitude weaker in both functional and binding assays. The successful synthesis of HomoAnTx with retention of high nicotinic potency offers a route for the generation of novel, potent radiolabelled nicotinic ligands.

Animals↗