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C R Ganellin

Publications and source records attributed to C R Ganellin.

At least 19 recordsLinked to original sources
PubMed1999

Novel partial agonists for the histamine H(3) receptor with high in vitro and in vivo activity.

Novel branched N-alkylcarbamates and aliphatic ethers derived from 3-(1H-imidazol-4-yl)propanol were prepared. The compounds were investigated on two functional histamine H(3)-receptor assays. Some compounds displayed partial agonist activity on synaptosomes of rat brain cortex but behaved as pure competitive antagonists on the guinea pig ileum. Under in vivo conditions after po application to mice, some of the compounds showed partial or full agonist activity. Highest in vivo potency was found for the 3,3-dimethylbutyl ether 10 (ED(50) = 0.29 mg/kg, full intrinsic activity). These novel agonists are structurally diverse from classical aminergic histamine H(3)-receptor agonists (e.g., (R)-alpha-methylhistamine, imetit) as they lack a basic moiety in the side chain, which is supposed to be important for the activation of the receptor protein. The selectivity for the histamine H(3) receptor was proven by determination of H(1)- and H(2)-receptor activity on functional assays of the guinea pig.

Animals↗
PubMed1999

Development of chiral N-alkylcarbamates as new leads for potent and selective H3-receptor antagonists: synthesis, capillary electrophoresis, and in vitro and oral in vivo activity.

Novel carbamates as derivatives of 3-(1H-imidazol-4-yl)propanol with an N-alkyl chain were prepared as histamine H3-receptor antagonists. Branching of the N-alkyl side chain with methyl groups led to chiral compounds which were synthesized stereospecifically by a Mitsunobu protocol adapted Gabriel synthesis. The optical purity of some of the chiral compounds was determined (ee > 95%) by capillary electrophoresis (CE). The investigated compounds showed pronounced to high antagonist activity (Ki values of 4.1-316 nM) in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes. Similar H3-receptor antagonist activities were observed in a peripheral model on guinea pig ileum. No stereoselective discrimination for the H3 receptor for the chiral antagonists was found with the in vitro assays. All compounds were also screened for central H3-receptor antagonist activity in vivo in mice after po administration. Most compounds were potent agents of the H3-receptor-mediated enhancement of brain Ntau-methylhistamine levels. The enantiomers of the N-2-heptylcarbamate showed a stereoselective differentiation in their pharmacological effect in vivo (ED50 of 0.39 mg/kg for the (S)-derivative vs 1.5 mg/kg for the (R)-derivative) most probably caused by differences in pharmacokinetic parameters. H1- and H2-receptor activities were determined for some of the novel carbamates, demonstrating that they have a highly selective action at the histamine H3 receptor.

Administration, Oral↗
PubMed1999

Differences in the actions of some blockers of the calcium-activated potassium permeability in mammalian red cells.

1. The actions of some inhibitors of the Ca2+-activated K+ permeability in mammalian red cells have been compared. 2. Block of the permeability was assessed from the reduction in the net loss of K+ that followed the application of the Ca2+ ionophore A23187 (2 microM) to rabbit red cells suspended at a haematocrit of 1% in a low potassium solution ([K]0 0.12-0.17 mM) at 37 degrees C. Net movement of K+ was measured using a K+-sensitive electrode placed in the suspension. 3. The concentrations (microM +/- s.d.) of the compounds tested causing 50% inhibition of K+ loss were: quinine, 37 +/- 3; cetiedil, 26 +/- 1; the cetiedil congeners UCL 1269, UCL 1274 and UCL 1495, approximately 150, 8.2 +/- 0.1, 0.92 +/- 0.03 respectively; clotrimazole, 1.2 +/- 0.1; nitrendipine, 3.6 +/- 0.5 and charybdotoxin, 0.015 +/- 0.002. 4. The characteristics of the block suggested that compounds could be placed in two groups. For one set (quinine, cetiedil, and the UCL congeners), the concentration-inhibition curves were steeper (Hill coefficient, nH, > or = 2.7) than for the other (clotrimazole, nitrendipine, charybdotoxin) for which nH approximately 1. 5. Compounds in the first set alone became less active on raising the concentration of K+ in the external solution to 5.4 mM. 6. The rate of K+ loss induced by A23187 slowed in the presence of high concentrations of cetiedil and its analogues, suggesting a use-dependent component to the inhibitory action. This was not seen with clotrimazole. 7. The blocking action of the cetiedil analogue UCL 1274 could not be overcome by an increase in external Ca2+ and its potency was unaltered when K+ loss was induced by the application of Pb2+ (10 microM) rather than by A23187. 8. These results, taken with the findings of others, suggest that agents that block the red cell Ca2+-activated K+ permeability can be placed in two groups with different mechanisms of action. The differences can be explained by supposing that clotrimazole and charybdotoxin act at the outer face of the channel whereas cetiedil and its congeners may block within it, either at or near the K+ binding site that determines the flow of K+.

Analgesics, Non-Narcotic↗
PubMed1998

Education of medicinal chemists in Departments of Medicinal Chemistry (U.S.A.).

The present state of faculties, student bodies, and curricula in departments of medicinal chemistry have been surveyed by questionnaire and analyzed in the context of perceptions of quality and content. The results reveal a healthy diversity of educational objectives and a broader range of educational objectives than those uncovered in previous surveys of the perceived needs of industrial departments of medicinal chemistry in their search for drug discovery personnel.

Chemistry, Pharmaceutical↗
PubMed1998

Synthesis of potent non-imidazole histamine H3-receptor antagonists.

Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N alpha-position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 microM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (Ki = 0.18 +/- 0.10 microM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki = 39 +/- 11 nM), ED50 = 1.1 +/- 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.

Administration, Oral↗
PubMed1998

Modulation of GABA(A) receptors and inhibitory synaptic currents by the endogenous CNS sleep regulator cis-9,10-octadecenoamide (cOA).

1. Cis-9,10-octadecenoamide (cOA) accumulates in the CSF of sleep-deprived cats and may represent a novel signalling molecule. Synthetic cOA has been shown to induce physiological sleep when injected into laboratory rats. Here we assess the cellular mode of action of cOA in vitro. 2. In all rat cultured cortical neurones (pyramidal cells) examined, the synthetic brain lipid (3.2-64 microM) enhanced the responses to subsaturating GABA concentrations (up to circa 2x) in a concentration-dependent manner (EC50, circa 15 microM). 3. (20 microM) cOA significantly enhanced the affinity of exogenous GABA for its receptor without changing the Hill slope or the maximal response. These effects were not voltage-dependent or secondary to shifts in E(Cl). 4. In the absence of GABA, cOA directly evoked small inhibitory currents in a subpopulation (<7%) of sensitive cells. 5. 20 microM cOA reversibly enhanced the duration of spontaneous inhibitory post synaptic currents (circa 2 fold) without significantly altering their amplitude. 6. At 32-64 microM, cOA reversibly reduced the incidence and amplitude of both inhibitory post synaptic currents (i.p.s.cs) and excitatory post synaptic currents (e.p.s.cs) in the cultured neuronal circuits in common with other depressant drugs acting at the GABA(A) receptor. 7. 32 microM Oleic acid did not modulate exogenous GABA currents or synaptic activity suggesting that cOAs actions are mediated through a specific receptor. 8. A specific, protein-dependent interaction with GABA(A) receptors was confirmed in Xenopus oocytes. Recombinant human receptors were modulated by 10 microM cOA (and diazepam) only when a gamma2 subunit was co-expressed with alpha1beta2: the cOA response was not sensitive to the specific benzodiazepine antagonist flumazenil (1 microM). 9. cOA may represent an endogenous ligand for allosteric modulatory sites on isoforms of GABA(A) receptors which are crucial for the regulation of arousal and have recently been implicated in the circadian control of physiological sleep.

Animals↗
PubMed1998

Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist.

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl) ketone, belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling [3H]histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with [125I]iodoproxyfan. Ciproxifan displayed at least 3-orders of magnitude lower potency at various aminergic receptors studied in functional or binding tests. In vivo, measurement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability ratio of 62%. Oral administration of ciproxifan to mice enhanced by approximately 100% histamine turnover rate and steady state level of tele-methylhistamine with an ED50 of 0.14 mg/kg. Ciproxifan reversed the H3-receptor agonist induced enhancement of water consumption in rats with and ID50 of 0.09 +/- 0.04 mg/kg, i.p. In cats, ciproxifan (0.15-2 mg/kg, p.o.) induced marked signs of neocortical electroencephalogram activation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.

Animals↗
PubMed1996

Synthesis, molecular modeling, and K+ channel-blocking activity of dequalinium analogues having semirigid linkers.

Dequalinium [1,1'-(decane-1, 10-diyl)bis(2-methyl-4-aminoquinolinium)] is an effective blocker of the small conductance Ca2(+)-activated K+ channel. It has been shown that the number of methylene groups in the alkyl chain linking the two quinolinium rings of this type of molecule is not critical for activity. To further investigate the role of the linker, analogues of dequalinium have been synthesized, in which the alkyl chain has been replaced by CH2XCH2 where X is a rigid or semirigid group containing aromatic rings. The compounds have been tested for blockade of the slow after-hyperpolarization on rat sympathetic neurons. The most potent compounds have X = phenanthryl, fluorenyl, cis-stilbene, and C6H4(CH2)nC6H4, where n = 0-4. The conformational preferences of the compounds were investigated using the XED/COSMIC molecular modeling system. Although there is some dependence of the potency of the analogue on the conformational properties of the linker (X), overall, X groups having substantial structural differences are tolerated. It seems that X provides a support for the two quinolinium groups and does not interact with the channel directly. The intramolecular separation between the quinolinium rings, which is provided by rigid groups X, is not critical for activity; this may be attributed to the residual conformational mobility of the heterocycles and to the extensive delocalization of the positive charge. These two factors may permit favorable contacts between the quinolinium groups and the channel over a range of intramolecular separations.

Animals↗
PubMed1996

A novel series of (phenoxyalkyl)imidazoles as potent H3-receptor histamine antagonists.

[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X = NH, S, CH2S, O) of previously described [[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X = NH, S) have been synthesized and evaluated for H3-receptor histamine antagonism in vitro (Ki for [3H]histamine release from rat cerebral cortex synaptosomes) and in vivo (ED50 per os in mice on brain tele-methylhistamine levels). Encouraging results led to the synthesis and testing of a novel series of substituted (phenoxyethyl)- and (phenoxypropyl)imidazoles. From the latter, 4-[3-(4-cyanophenoxy)propyl]-1H-imidazole (10a, UCL 1390; Ki = 12 nM, ED50 = 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)-phenoxy]propyl]-1H-imidazole (10c, UCL 1409; Ki = 14 nM, ED50 = 0.60 mg/kg) have been selected as potential candidates for drug development. For 16 [(aryloxy)ethyl]imidazoles the relationship between in vitro and in vivo potency is described by the equation log ED50 = 0.47 log Ki + 0.20 (r = 0.78).

Animals↗
PubMed1996

Synthesis and pharmacological testing of dequalinium analogues as blockers of the apamin-sensitive Ca(2+)-activated K+ channel: variation of the length of the alkylene chain.

Dequalinium is a potent and selective blocker of the small conductance Ca(2+)-activated K+ (SKCa) channel in rat sympathetic neurones. Analogues of dequalinium possessing 3-6, 8, 10, and 12 methylene groups in the linking chain have been synthesized and tested for inhibition of the afterhyperpolarization in rat sympathetic neurones. The compounds having a 5-12-carbon chain showed very little variation in their activity as SKCa channel blockers. The analogues possessing four and three methylenes exhibited 3- and 8-fold lower potency, respectively, compared with dequalinium. These results are discussed in the context of possible modes of binding of the compounds to the SKCa channel.

Action Potentials↗
PubMed1996

Photolabile derivatives of 125I-apamin: defining the structural criteria required for labeling high and low molecular mass polypeptides associated with small conductance Ca(2+)-activated K+ channels.

The structure of apamin-sensitive Ca(2+)-activated K+ channels has been investigated using high-affinity, photolabile azidoaryl derivatives of 125I-[alpha-formyl-Cys1]apamin and 125I-[epsilon-formyl-Lys4]-apamin. Labeling patterns suggest that similar structural constraints are required for labeling analogous polypeptides associated with distinct channel subtypes. When photoprobes are coupled at the epsilon-amino-Lys4 position of apamin, comparable low molecular mass (approximately 30 kDa) polypeptides are efficiently labeled on either brain or liver plasma membranes, irrespective of the structure of the photoprobe. However, when photoprobes are coupled at the alpha-amino-Cys1 position of apamin, the pattern of labeling on both brain and liver plasma membranes varies, depending upon the length of the spacer arm incorporated into the photoprobe. Spacer arms of approximately 8-9 A efficiently label only high molecular mass polypeptides (86, 59 kDa), accompanied by weak, variable labeling of a 44-kDa component. A shorter spacer arm (5.7 A) results in feeble labeling of 86- and 59-kDa polypeptides and barely detectable labeling of 44- and approximately 30-kDa polypeptides. In contrast, a long spacer arm (12.8 A) efficiently labels only approximately 30-kDa polypeptides. These findings point to close similarities in the topography of the 125I-apamin binding site present on pharmacologically distinct subtypes of apamin-sensitive Ca2+-activated K+ channels and indicates that heterooligomeric association of high and low molecular mass polypeptide subunits may be a general structural feature of members belonging to this family of K+ channels.

Animals↗
PubMed1996

Characterization and inhibition of a cholecystokinin-inactivating serine peptidase.

A cholecystokinin (CCK)-inactivating peptidase was purified and identified as a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10), a cytosolic subtilisin-like peptidase of previously unknown functions. The peptidase was found in neurons responding to cholecystokinin, as well as in non-neuronal cells. Butabindide, a potent and specific inhibitor, was designed and shown to protect endogenous cholecystokinin from inactivation and to display pro-satiating effects mediated by the CCKA receptor.

Amino Acid Sequence↗
PubMed1996

Synthesis and quantitative structure-activity relationship of a novel series of small conductance Ca(2+)-activated K+ channel blockers related to dequalinium.

The synthesis, pharmacological testing, and quantitative structure-activity relationship studies of a novel series of bisquinolinium small conductance Ca(2+)-activated K+ channel blockers (23) related to dequalinium are described. In this series, two quinolinium rings are linked via the 4-position to an alpha, omega-diamino alkylene chain and the ring N atom is quaternized with a methyl or benzyl group. The exocyclic N atom can be replaced by O, S, or CH2 but with some loss of potency. The quinoline groups do not have to be quaternized for blocking activity, as long as they are basic enough to be protonated at the site of action. For the quaternary compounds, there is considerable steric tolerance for the group R attached to the ring N atom of the quinoline; a benzyl group gave the optimum potency in this series. Moreover, and in contrast to previously reported results for dequalinium analogues, there is no correlation of activity to previously reported results for dequalinium analogues, there is no correlation of activity with N1 charge or EHOMO. On the other hand, a good correlation was obtained between the blocking potency of the compounds and ELUMO [pEMR = 1.16(+/-0.26)ELUMO + 5.33(+/-01.29)(n = 11, r= 0.83, s = 0.243)]. It has been possible to combine this equation with the previously reported ELUMO correlation for a series of dequalinium analogues to include all the compounds of both series [pEMR = 1.17(+/-0.15)ELUMO +5.33(+/-0.76)(n =24, r = 0.85, s = 0.249)]. A possible physical meaning for the ELUMO correlation based upon the principle of maximum hardness is discussed.

Animals↗
PubMed1996

On the concept of a bivalent pharmacophore for SKCa channel blockers: synthesis, pharmacological testing, and radioligand binding studies on mono-, bis-, and tris-quinolinium compounds.

The dissociation equilibrium constants (Kd values) of dequalinium (2) and the monoquinolinium compounds 1a and 1b have been determined from competition equilibrium radioligand binding with [125I]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the channel with 2 orders of magnitude higher affinity than 1a or 1b, suggesting that both quinolinium groups are needed for potent and selective SKCa channel blockade. The trisquinolinium compound 3 (1,1'-[5-[4-(4- aminoquinolinium-1-yl)but-1-yl]non-4-en-1,9-diyl]-bis-(4- aminoquinolinium)) has been synthesized and tested for inhibition of the afterhyperpolarization of rat sympathetic neurones and on the binding assay. Compound 3 shows approximately one order of magnitude higher potency than 2, being the most potent non-peptidic SKCa channel blocker reported so far (Kd approximately 30 nM). The higher affinity of 3 compared with 2 may be due to direct binding of the third quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the "local concentration" of quinolinium groups.

Animals↗
PubMed1996

Discrimination between subtypes of apamin-sensitive Ca(2+)-activated K+ channels by gallamine and a novel bis-quaternary quinolinium cyclophane, UCL 1530.

1. Gallamine, dequalinium and a novel bis-quaternary cyclophane, UCL 1530 (8,19-diaza-3(1,4),5(1,4)-dibenzena-1 (1,4),7(1,4)-diquinolina-cyclononadecanephanedium) were tested for their ability to block actions mediated by the small conductance, apamin-sensitive Ca(2+)-activated K+ (SKCa) channels in rat cultured sympathetic neurones and guinea-pig isolated hepatocytes. 2. SKCa channel block was assessed in sympathetic neurones by the reduction in the slow afterhyperpolarization (AHP) that follows an action potential, and in hepatocytes by the inhibition of the SKCa mediated net loss of K+ that results from the application of angiotensin II. 3. The order of potency for inhibition of the AHP in sympathetic neurones was UCL 1530 > dequalinium > gallamine, with IC50 values of 0.08 +/- 0.02, 0.60 +/- 0.05 and 68.0 +/- 8.4 microM respectively, giving an equi-effective molar ratio between gallamine and UCL 1530 of 850. 4. The same three compounds inhibited angiotensin II-evoked K+ loss from guinea-pig hepatocytes in the order dequalinium > UCL 1530 > gallamine, with an equi-effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympathetic neurones. 5. Dequalinium and UCL 1530 were as effective on guinea-pig as on rat sympathetic neurones. 6. UCL 1530 at 1 microM had no effect on the voltage-activated Ca2+ current in rat sympathetic neurones, but inhibited the hyperpolarization produced by direct elevation of cytosolic Ca2+. 7. Direct activation of SKCa channels by raising cytosolic Ca2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with dequalinium being the most potent. 8. These results provide evidence that the SKCa channels present in guinea-pig hepatocytes and rat cultured sympathetic neurones are different, and that this is not attributable to species variation. UCL 1530 and gallamine should be useful tools for the investigation of subtypes of apamin-sensitive K+ channels.

Alkanes↗
PubMed1996

The synthesis and some pharmacological actions of the enantiomers of the K(+)-channel blocker cetiedil.

Cetiedil ((+/-)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1 H-azepin-1-yl) ethyl ester) possesses anti-sickling and analgesic, antispasmodic, local anaesthetic and vasodilator activities. A total synthesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as blockers of the Ca(2+)-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca(2+)-dependent contraction of depolarized intestinal muscle; and the cell volume-sensitive K+ permeability (Kvol) of liver cells. The enantiomers did not differ substantially in their ability to block the Ca(2+)-activated K+ permeability of rabbit red cells or in their effectiveness as blockers of the contractile response of depolarized smooth muscle to externally applied Ca2+. There was a clear difference in the muscarinic blocking activity of the enantiomers, as assessed by inhibition of the contractile response of intestinal smooth muscle to acetylcholine; (+)-cetiedil was 7.7 +/- 0.2 (s.d.) times more active than the (-) from. The enantiomers also differed in their potency as blockers of the increase in membrane conductance which occurs when liver cells swell. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04 +/- 0.54 (s.d.) microM; (-)-cetiedil was 2.6 +/- 0.8 (s.d.) times less active (IC50 of 5.2 +/- 1.2 microM). Differences in the biological actions of the enantiomers of cetiedil indicate that a more extensive study could be rewarding in relation to the use of the enantiomers both in therapeutics and in the study of K+ channels.

Animals↗