Quinoline Hydrochloride Research Articles

Molluscicidal and Larvicidal Potency of N-Heterocylic Analogs against Biomophalaria alexandrina Snails and Schistosoma mansoni Larval Stages.

This work describes the synthesis of quinoline-based N--heterocyclic arenes and their biological evaluation as molluscicides against adult Biomophalaria alexandrina snails as well as larvicides against Schistosoma mansoni larvae (miracidia and cercariae). Molecular docking studies were demonstrated to investigate their affinity for cysteine protease protein as an interesting target for antiparasitics. Compound AEAN showed the best docking results followed by APAN in comparison to the co-crystallized ligand D1R reflected by their binding affinities and RMSD values. The egg production, hatchability of B. alexandrina snails and ultrastructural topography of S. mansoni cercariae using SEM were assessed. Biological evaluations (hatchability and egg-laying capacity) revealed that the quinoline hydrochloride salt CAAQ was the most effective compound against adult B. alexandrina snails, whereas the indolo-quinoline derivative APAN had the most efficiency against miracidia, and the acridinyl derivative AEAA was the most effective against cercariae and caused 100% mortality. CAAQ and AEAA were found to modulate the biological responses of B. alexandrina snails with/without S. mansoni infection and larval stages that will affect S. mansoni infection. AEAA caused deleterious morphological effects on cercariae. CAAQ caused inhibition in the number of eggs/snail/week and reduced reproductive rate to 43.8% in all the experimental groups. CAAQ and AEAA can be recommended as an effective molluscicide of plant origin for the control program of schistosomiasis.

Oncotoxic Properties of Serotonin Transporter Inhibitors and 5-HT1A Receptor Ligands

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.

Preparation of Pincer 4-Functionalized 2-Aminomethylbenzo[h]quinoline Ruthenium Catalysts for Ketone Reduction

Reaction of 1-naphthylamine with ethyl benzoylacetate gives the corresponding benzoyl acetamide derivative 1, which undergoes cyclization to 4-phenylbenzo[h]quinolin-2(1H)-one (2) in the presence of H2SO4. Bromination with POBr3, followed by reaction with n-BuLi and DMF, gives 4-phenylbenzo[h]quinoline-2-carbaldehyde (4), which is converted to the corresponding oxime hydrochloride 5 with NH2OH·HCl. Hydrogenation of 5 catalyzed by 10% Pd/C (type 338) leads to 4-phenyl-2-aminomethylbenzo[h]quinoline hydrochloride (HCNNPh·HCl, 6) isolated in high yield. Similarly, the 4-methyl-2-aminomethylbenzo[h]quinoline derivative (HCNNMe·HCl, 12) is prepared starting from 1-naphthylamine and 2,2,6-trimethyl-4H-1,3-dioxin-4-one, following the route for 6. Reaction of RuCl2(PPh3)3 with a diphosphine (PP), the HCl salt 6, and NEt3 in 2-propanol leads to the pincer complexes RuCl(CNNPh)(PP) (PP = Ph2P(CH2)3PPh2, 13; Ph2P(CH2)4PPh2, 14; 1,1′-bis(diphenylphosphino)ferrocene, 15). The methyl derivatives RuCl(CNNMe)(PP) (PP = P...

Investigation of the role of i1- and i2-imidazoline receptors in the mechanіsm of the hypoglycemic action of n,n’-(ethane-1,2 dyyil)bis(quinoline- 2-carboxamide)

The results of the investigation of the hypoglycemic action mechanism of N,N’-(ethane-1,2-dyyil)bis (quinoline-2-carboxamide) are presented. The substance was administered intragastrically in the dose of 11.64 mg/kg on the model of alloxan-induced diabetes mellitus in rats. It should be noted that the test compound in terms of the theory of pharmacophore can be considered as a dimer BU 224, but it is not its dimer in terms of organic chemistry. The information about the influence of the test compound on carbohydrate metabolism is limited. There are data that this compound has antitumor properties іn vitro due to enhanced apoptosis and activation of caspase-3. Proceeding from the chemical structure, the 2-substituted quinoline fragment is present in the structure of the known antagonist of imidazoline receptors I 2 such as 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride, so it can be assumed that N,N’-(ethane-1,2-dyyil)bis(quinoline-2-carboxamide) has the ability to interfere with the mechanisms of the carbohydrate metabolism regulation. These results indicate that N,N’-(ethane-1,2-dyyil)bis(quinolin-2-carboxamide) has an expressed hypoglycemic effect in alloxan-induced diabetes mellitus reducing the blood glucose level by 71.50%. It is an agonist of imidazoline receptors of both types, and it has been proven by blockade with selective antagonists such as efaroxan and 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride. On the background of I 1 -imidazoline receptors blocker efaroxan the glycemia decrease was 45.66% (p<0.05), and on the background of I2-imidazoline receptors blocker 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride it was 54.01% (p<0.05). Diabetes mellitus (DM) type 2 is a chronic disease caused by decrease in sensitivity of the human tissues to insulin [1, 14]. The frequency of diabetes on average ranges from 1.5% to 3%; it is constantly increasing in the developed countries up to 5-7%, in Ukraine the value is twice lower – about 2.9%. There are about 200 million of diabetics in the world; almost 90% of them suffer from type 2 diabetes [5, 15]. The urgency of DM problem is caused by a signifi cant prevalence of the disease, severity of complications, disability and early mortality. Microangiopathies and neuropathies are the basis of diabetic complications. The patients with diabetes have a significant risk of athero sclerosis and coronary heart disease. More than 40% of amputations of lower limbs are a consequence of the diabetic foot syndrome. Diabetes is also the most common cause of blindness in humans [12, 17]. All mentioned above stipulates the necessity of development and research of new effective drugs with the hypoglycemic effect allowing to prevent development of the severe course of DM. The mechanism of action of different antidiabetic drugs consists of a several links. There are data on the role of imidazoline receptors in implementation of the hypoglycemic effect, in particular for biguanides derivatives such as metformin [7]. Imidazoline receptors are the independent type of receptors represented by two subtypes: 11 and 12. Subtypes are distinguished according to the specific ligands that bind with them. Imidazoline receptors mediate the following effects: increase of glucose-dependent insulin release and transport of glucose into the cells and, as a result, decrease of hyperglycemia, improvement of the

Acute toxicity and the hypoglycemic action of n,n΄-(ethane-1,2-dyyil)bis(quinoline-2-carboxamide)

The results of the study of N,N΄-(ethane-1,2-dyyil)bis(quinoline-2-carboxamide) as a potential hypoglycemic agent on the model of alloxan diabetes, as well as in normoglycemic rats are presented, the “dose – effect” relationship and acute toxicity in various routes of administration have been determined. Proceeding from the theory of pharmacophores the test compound can be considered as a dimer of 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU 224), a blocker of I2-imidazoline receptors, but it is not a dimer in terms of organic chemistry. It has a strong hypoglycemic effect in intragastric administration in the dose range of 7.92-31.67 mg/kg. The maximum hypoglycemic effect is provided by the dose of 15.84 mg/kg. ED50 equals 11.64 mg/kg, the therapeutic index is 54.42 indicating a sufficient breadth of the therapeutic effect and safety of the test compound. In normoglycemia N,N΄-(ethane-1,2-dyyil)bis(quinoline-2-carboxamide) decreases the blood glucose level at the dose of 15.84 mg/kg, while the doses of 3.96 mg/kg and 7.92 mg/kg do not affect the blood glucose level, and it indicates that the features of pharmacodynamics and the hypoglycemic effect depend on the state of the carbohydrate metabolism. It has been shown that in hyperglycemia the hypoglycemic effect is observed starting at the dose of 7.92 mg/kg, and higher doses. However, in healthy animals, the aforesaid dose does not affect the blood glucose level. In the intraperitoneal administration the hypoglycemic effect is evident at the lower dose of 1.5 mg/kg exceeding metformin at the dose of 100 mg/kg by its hypoglycemic activity. In the intraperitoneal administration N,N΄-(ethane-1,2-dyyil)bis(quinoline-2-carboxamid) belongs to moderately toxic substances (toxicity of class III, LD50 = 10.005 mg/kg), in the intragastric administration – to low-toxic substances (toxicity of class IV, LD50 = 633.45 mg/kg).

Chronic treatment with selective I2-imidazoline receptor ligands decreases the content of pro-apoptotic markers in rat brain

Selective I(2)-imidazoline receptor ligands induce neuroprotection through various molecular mechanisms including blockade of N-methyl-D-aspartate (NMDA) receptors. To investigate new neuroprotective mechanisms associated with I(2)-imidazoline receptors, the effects of selective (2-styryl-2-imidazoline (LSL 61122), 2-(2-benzofuranyl)-2-imidazoline (2-BFI), 2-(4,5-dihydroimidazol-2-yl) quinoline hydrochloride (BU-224)) and non-selective (idazoxan) I(2)-drugs on canonical apoptotic pathways were assessed in rat brain cortex. The acute treatment with LSL 61122 (10 mg/kg) reduced the content of mitochondrial (pro-apoptotic) Bax (-33%) and cytochrome c (-31%), which was prevented by idazoxan, an I(2)-receptor antagonist. The sustained stimulation of I(2)-imidazoline receptors with selective drugs (10 mg/kg, every 12 h for seven days) was associated with down-regulation of key components of the extrinsic (Fas receptor: -20%; Fas associated protein with death domain (FADD) adaptor: -47-54%) and/or intrinsic (Bax: -20-23%; cytochrome c: -22-28%) apoptotic signalling and/or up-regulation of survival anti-apoptotic factors (p-Ser194 FADD/FADD ratio: +1.6-2.5-fold; and/or Bcl-2/Bax ratio: +1.5-fold), which in the long-term could dampen cell death in the brain. Similar chronic treatments with LSL 60101 (the imidazole analogue of 2-BFI) and idazoxan (a mixed I(2)/α(2)-ligand) did not induce significant alterations of pro- or anti-apoptotic proteins. The disclosed anti-apoptotic mechanisms of selective I(2)-imidazoline drugs may work in concert with other molecular mechanisms of neuroprotection (e.g. blockade of NMDA receptors) that are engaged by I(2)-ligands.

Effects of imidazoline I2 receptor ligands on morphine- and tramadol-induced antinociception in rats

Currently available analgesics cannot meet the increasing clinical needs and new analgesics with better therapeutic profiles are in great demand. The imidazoline I₂ receptor is an emerging drug target for analgesics. However, few studies have examined the effects of selective I₂ receptor ligands on the antinociceptive activity of opioids. This study examined the antinociceptive effects of the opioids morphine (0.1-10 mg/kg) and tramadol (3.2-56 mg/kg), the nonselective I₂ receptor ligand agmatine (10-100 mg/kg), and the selective I₂ receptor ligands 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI; 1-10 mg/kg) and 2-(4, 5-dihydroimidazol-2-yl) quinoline hydrochloride (BU224; 1-10mg/kg), alone and in combination, in a warm water tail withdrawal procedure in rats. Morphine and tramadol but not agmatine, 2-BFI or BU224 increased tail withdrawal latency in a dose-related manner at 48°C water. Agmatine and 2-BFI but not BU224 dose-dependently enhanced the antinociceptive effects of morphine and tramadol, shifting the dose-effect curves of morphine and tramadol leftward. The enhancement of agmatine and 2-BFI on morphine and tramadol antinociception was prevented by BU224. These results, combined with the fact that BU224 and 2-BFI share similar behavioral effects under other conditions, suggest that BU224 has lower efficacy than 2-BFI at I₂ receptors, and that the enhancement of opioid antinociception by I₂ receptor ligands depends on their efficacies.

Synthesis and biological study of novel 5-{(4-(6,7-dihydrothieno-[3,2-c]pyridin-5(4H)-ylsulfonyl)phenylamino)-methyl}quinolin-8-ol and its metal complexes

Abstract A novel 5-((4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)phenylamino)methyl)quinolin-8-ol (HTPSMQol) was synthesized by optimized reaction of 4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-ylsulfonyl)aniline with 5-chloromethyl-8-hydroxy quinoline hydrochloride (CMHQ). Also complexes of HTPSMQol were prepared by using various M (II) metal salts. All compounds were analyzed by spectroscopic techniques and screened against various strains of microorganisms. The results showed higher antimicrobial activity of HTPSMQol compared to its metal complexes and comparable with Ciprofloxacin.

Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT(2C) receptor-selective agonist vabicaserin [(-)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT(2B) receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced (125)I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT(2C) receptor sites in Chinese hamster ovary cell membranes with a K(i) value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT(2B) receptor subtype using [(3)H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC(50), 8 nM; E(max), 100%) in stimulating 5-HT(2C) receptor-coupled calcium mobilization and exhibited 5-HT(2A) receptor antagonism and 5-HT(2B) antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT(2B) receptors, vabicaserin failed to induce a 5-HT(2B) receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT(2B) competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT(2B) receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT(2B) receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT(2B) receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT(2C) receptor agonist.

Novel aminated benzimidazo[1,2- a]quinolines as potential fluorescent probes for DNA detection: Microwave-assisted synthesis, spectroscopic characterization and crystal structure determination

A synthesis of novel benzimidazo[1,2- a]quinolines, substituted with piperidine, pyrrolidine and piperazine nuclei has been accomplished using an uncatalyzed amination protocol under microwave heating. All compounds were characterized by means of 1H, 13C NMR, IR, UV/Vis and fluorescence spectroscopy. Crystal and molecular structures of 2-chloro- and 2-piperidinyl-benzimidazo[1,2- a]quinoline-6-carbonitrile were determined by X-ray diffractometry. These molecules are essentially planar. Their molecular assembly is characterized by the existence of weak intermolecular hydrogen bonds of C–H⋅⋅⋅N type and π–π aromatic interactions. The π–π aromatic stacking observed in the solid state structures of the 2-chloro- and 2-piperidinyl- derivatives are not analogous. The spectroscopic properties of these amino substituted benzimidazo[1,2- a]quinolines as their hydrochloride salts in the presence of ct-DNA were studied by means of fluorescence spectroscopy. Comparison of binding properties of amino substituted benzimidazo[1,2- a]quinoline hydrochloride salts to ct-DNA revealed significantly enhanced fluorescence emission intensity and thus offer the potential applications as a DNA-specific fluorescent probes.

ChemInform Abstract: Stereoselective Synthesis and Optical Resolution of Chiral Calix(4)arenes with Mixed Ligating Functionalities.

Exhaustive alkylation of syn-proximal bis[(2-pyridylmethyl)oxy]calix[4]arene 1 with t-butyl bromoacetate or 2-(chloromethyl)quinoline hydrochloride in the presence of Cs2CO3 affords selectively a new type of inherently chiral calix[4]arenes 2a,b in the partial cone conformation. (±) 2b has been resolved into its optical antipodes by an HPLC method.

Pharmacological characterization of the inhibition by moxonidine and agmatine on the cardioaccelerator sympathetic outflow in pithed rats

This study analysed the inhibition produced by the agonists moxonidine (imidazoline I 1 receptors > α 2-adrenoceptors) and agmatine (endogenous ligand of imidazoline I 1/I 2 receptors), using B-HT 933 (6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepin-2-amine dihydrochloride; α 2-adrenoceptors) for comparison, on the rat cardioaccelerator sympathetic outflow. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. Sympathetic stimulation or noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. I.v. continuous infusions of moxonidine (3 and 10 µg/kg min), agmatine (1000 and 3000 µg/kg min) and B-HT 933 (30 and 100 µg/kg min) inhibited the tachycardic responses to sympathetic stimulation, but not those to noradrenaline. The cardiac sympatho-inhibition by either moxonidine (3 µg/kg min) or B-HT 933 (30 µg/kg min) was not modified by i.v. injections of saline or the antagonists AGN192403 [(±)-2-endo-Amino-3-exo-isopropylbicyclo[2.2.1]heptane hydrochloride; 3000 µg/kg; imidazoline I 1 receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 µg/kg; imidazoline I 2 receptors) and abolished by rauwolscine (300 µg/kg; α 2-adrenoceptors). At the same doses of these compounds, the sympatho-inhibition to moxonidine (10 µg/kg min) and agmatine (1000 µg/kg min) was: (1) not modified by saline, AGN192403 or BU224; (2) partially blocked by rauwolscine or the combination of rauwolscine plus BU224; and (3) abolished by the combination of rauwolscine plus AGN192403. These results demonstrate that the cardiac sympatho-inhibition to: (1) 3 µg/kg min moxonidine or 30 µg/kg min B-HT 933 involves α 2-adrenoceptors; and (2) 10 µg/kg min moxonidine or 1000 µg/kg min agmatine involves α 2-adrenoceptors and imidazoline I 1 receptors.

Cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is required for the reinstatement of cocaine-seeking behavior in the rat

Activation of D1-like (D1, D5) or D2-like (D1, D3, D4) dopamine receptors in the nucleus accumbens shell is sufficient to reinstate cocaine-seeking behavior in rats. The goal of these experiments was to assess whether cooperative activation of D1-like and D2-like dopamine receptors in the accumbens shell is required to promote cocaine reinstatement. Rats were initially trained to self-administer cocaine (0.25 mg, i.v.) using a fixed-ratio schedule of reinforcement for approximately 21 days. Animals subsequently underwent an extinction phase during which saline was substituted for cocaine. Once cocaine self-administration behavior was extinguished (defined as <15% of the total responses maintained during self-administration), dopamine receptor agonist-induced reinstatement of cocaine seeking was assessed. Administration of the selective D1/5 agonist R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) (1.0 μg) or the D2/3 receptor agonist trans-(−)-(4aR)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole) (3.0 μg) directly into the nucleus accumbens shell promoted reinstatement of cocaine seeking. In order to determine if endogenous dopamine tone in the accumbens shell is required for dopamine receptor agonist-induced reinstatement of cocaine seeking, D1/5 or D2/3 dopamine receptor antagonists were administered into the nucleus accumbens shell prior to a selective dopamine receptor agonist. Microinfusion of the D2/3 dopamine receptor antagonist sulpiride (( S)-5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide) (1.0 μg) into the nucleus accumbens shell 10 minutes prior to SKF-81297 (1.0 μg) blocked the ability of this D1-like dopamine receptor agonist to reinstate cocaine seeking. Similarly, administration of the selective D1/5 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (1.0 μg) into the nucleus accumbens shell prior to quinpirole (3.0 μg) blocked reinstatement of drug-seeking behavior elicited by this D2/3 dopamine receptor agonist. Moreover, intra-accumbal shell co-administration of subthreshold doses of quinpirole (1.5 μg) and SKF-81297 (0.1 μg) promoted cocaine-seeking behavior. Collectively, these results indicate that cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is necessary to reinstate cocaine seeking in rats.

2-(2-aminoethyl)-quinoline (D-1997): A Novel Agonist at Craniovascular 5-HT1 Receptors Relevant to Migraine Therapy

The functional pharmacological properties of a group of quinoline-derivatives were screened for agonist activity at 5-HT1-like receptors mediating vasoconstriction. In experimental models predictive of antimigraine activity, 2-(2-aminoethyl) quinoline hydrochloride (D-1997) exhibited higher potency and efficacy at vasoconstrictor 5-HT1-like receptors than quipazine. D-1997 was also found to activate a novel vasoconstrictor mechanism in the carotid circulation. It is suggested D-1997 may represent a useful lead in the search for better acute antimigraine therapies.

Synthesis of Novel 2‐Nitroimidazole‐Tethered Tricyclic Quinolines, Bearing a Second Heteroatom, and Their in vitro Evaluation as Hypoxia‐Selective Cytotoxins and Radiosensitizers.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of novel 2-nitroimidazole-tethered tricyclic quinolines, bearing a second heteroatom, and their in vitro evaluation as hypoxia-selective cytotoxins and radiosensitizers

Two novel nitroimidazole-based bioreductive compounds, 10-[3-(2-nitroimidazolyl)-propylamino]-3,4-dihydro-1 H-thiopyrano[4,3- b]quinoline hydrochloride ( 8a) and 10-[3-(2-nitroimidazolyl)propylamino]-2-methyl-1,2,3,4-tetrahydro-benzo[ b]-1,6-naphthyridine hydrochloride ( 8b) have been synthesized and evaluated in V79 cells as hypoxia-selective cytotoxins and radiosensitizers that target DNA through weak intercalation. Both compounds were relatively good radiosensitizers (C 1.6 values of 40.0±0.8 and 59.0±0.4 μM for 8a and 8b, respectively) but neither of the compounds was superior to 2 which does not carry a second heteroatom in the DNA-intercalating chromophore.

Quinone Imines with a Fused Azine Ring: I. Synthesis and Hydrochlorination of 5-(p-Tolylsulfonylimino)quinolin-8-one

5-(p-Tolylsulfonylimino)quinolin-8-one was synthesized, and its reaction with hydrogen chloride was studied. The reaction leads to formation of 7-chloro-8-hydroxy-5-(p-tolylsulfonylamino)quinoline hydrochloride.

Potentiation effects of (±)huprine X, a new acetylcholinesterase inhibitor, on nicotinic receptors in rat cortical synaptosomes

The present experiments were developed to analyze the direct and/or potentiation effect of (±)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[ b]quinoline hydrochloride ((±)huprine X) on nicotinic receptors using a synaptosomal superfusion method. (±)Huprine X (1 μM, 10 μM) increased [ 3H]-ACh release only at 10 μM (46%; P<0.001) in basal, but not in stimulated, conditions. This effect was completely reverted by mecamylamine (100 μM; MEC). Potentiation of evoked-[ 3H]-ACh release induced by ACh (1 μM) and by galantamine (GAL) 0.4 μM and physostigmine (PHY) 10 μM (55% and 50%, respectively; P<0.001), two well-known allosteric compounds, corroborate that the present experimental approach is a suitable method to study potentiation effects on nicotinic receptors in the central nervous system nerve terminals. (±)Huprine X potentiated the evoked-[ 3H]-ACh release induced by ACh (1 μM) by 166% and 90% ( P<0.001) at 10 μM and 30 μM, respectively, and this effect was completely blocked by MEC (100 μM). In the presence of different ACh concentrations, (±)huprine X 10 μM potentiated evoked-[ 3H]-ACh release at low ACh concentrations, while a decrease in neurotransmitter release was observed at high ACh concentrations. The highest potentiation effect was obtained at the ACh/(±)huprine X concentration ratio of 1:10, and this potentiation was observed at as low a (±)huprine X concentration as 0.1 μM ( P<0.05). While the results suggest that huprine may enhance the potency or effectiveness of ACh by an effect involving nicotinic receptors we cannot completely discard that the results could be explained by acetylcholine esterase inhibition.

Direct and indirect actions of dopamine on the membrane potential in medium spiny neurons of the mouse neostriatum.

Many studies have shown dopamine (DA) to have a modulatory effect on neuronal excitability, which cannot be simply classified as excitatory or inhibitory in the neostriatum. To clarify whether the responses to DA (10-30 microM) are excitatory or inhibitory in the mouse medium spiny neurons, we examined the effects of DA agonists on the synchronous potential trajectory from the resting potential to the subthreshold potential. The DA-induced potential changes, which were estimated at the subthreshold potential (approximately -60 mV), were summarized as the combination of three kinds of responses: an initial hyperpolarization lasting approximately 1 min and a slow depolarization and/or hyperpolarization lasting more than 20 min. A D(1)-like receptor agonist, R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF81297, 1 microM) mainly induced the initial hyperpolarization and slow depolarization. A D(2)-like receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole, 1 microM), mainly induced the initial hyperpolarization and slow hyperpolarization. D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390, 1 microM) depressed both the initial hyperpolarization and slow depolarization. D(2)-like receptor antagonist sulpiride (1 microM) depressed all the DA-induced responses except for the slow depolarization. TTX (0.5 microM) abolished all the DA-induced responses. Bicuculline (20 microM) and atropine (1 microM) abolished the DA-induced initial hyperpolarization and slow depolarization, respectively. Either DL-2-amino-5-phosphonopentanoic acid (AP5; 100 microM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20 microM) blocked both the initial hyperpolarization and slow depolarization. The application of exogenous glutamate (Glu) mimicked the initial hyperpolarization and slow depolarization. These results suggest that the initial hyperpolarization is mainly due to GABA release via the cooperative action of D(1)- and D(2)-like receptors and Glu receptors in GABAergic interneurons, whereas the slow depolarization is mediated by acetylcholine (ACh) release via the cooperative action of mainly D(1)-like receptors and Glu receptors in cholinergic interneurons. The potential oscillation was generated at the subthreshold level in a Ba(2+)-, AP5-, CNQX-, bicuculline-, and atropine-containing medium. The oscillation depressed after the addition of TTX, Co(2+), or DA. In DA agonists, quinpirole rather than SKF81297 had a more depressive effect on the potential oscillation. These results indicate that the slow hyperpolarization is due to the suppression of noninactivating Na(+)-Ca(2+) conductances via mainly D(2)-like receptors in the medium spiny neurons. In conclusion, the DA actions on the medium spiny neurons show a transient inhibition by the activation of D(1)- and D(2)-like receptors in mainly GABAergic interneurons and a tonic excitation and/or inhibition by the activation of mainly D(1)-like receptors in cholinergic interneurons and by the activation of mainly D(2)-like receptors in the medium spiny neurons, respectively.

The pharmacology of novel acetylcholinesterase inhibitors, (±)-huprines Y and X, on the Torpedo electric organ

The effects of the tacrine–huperzine A hybrid acetylcholinesterase inhibitors, (±)-12-amino-3-chloro-9-methyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[ b]quinoline hydrochloride ((±)-huprine Y) and (±)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[ b]quinoline hydrochloride ((±)-huprine X), were tested on spontaneous synaptic activity by measuring the amplitude, the rise time, the rate of rise, the half-width and the area or the electrical charge of the miniature endplate potentials (m.e.p.ps) recorded extracellularly on Torpedo electric organ fragments. (±)-Huprine Y and (±)-huprine X at a concentration of 500 nM increased all the m.e.p.p. variables analyzed. The effect of (±)-huprine Y was smaller than that of (±)-huprine X for all the variables except for the rate of rise where there was no significant difference. The effects of these drugs were also tested on nicotinic receptors by analyzing the currents elicited by acetylcholine (100 μM) in Xenopus laevis oocytes, transplanted with membranes from Torpedo electric organ. Both drugs inhibited the currents in a reversible manner, (±)-huprine Y (IC 50=452 nM) being more effective than (±)-huprine X (IC 50=4865 nM). The Hill coefficient was 0.5 for both drugs. The inhibition of the nicotinic receptor was voltage-dependent and decreased at depolarizing potentials, and there was no significant difference in the effects between (±)-huprine Y and (±)-huprine X at concentrations near to their IC 50 values. At depolarizing potentials between −20 and +15 mV, these drugs did not have any detectable effect on the blockade of the nicotinic receptor. Both huprines increased the desensitization of the nicotinic receptors since the current closed quickly in the presence of the drugs, and there was no significant difference in this effect between (±)-huprine Y (500 nM) and (±)-huprine X (5 μM). We conclude that (±)-huprine Y and (±)-huprine X increase the level of acetylcholine in the synaptic cleft more effectively than tacrine. The interaction of (±)-huprine X with nicotinic receptors is weaker than that of (±)-huprine Y, suggesting that (±)-huprine X would be more specific to maintain the extracellular acetylcholine concentration.