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2.
J Cell Mol Med ; 16(8): 1758-65, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22004558

ABSTRACT

Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn(++)--chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4--but not (R)-2--caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy.


Subject(s)
Apoptosis/drug effects , Benzodiazepines/toxicity , Histone Deacetylase Inhibitors/toxicity , Hydroxamic Acids/toxicity , Acetylation/drug effects , Animals , Benzodiazepines/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Fluorometry , Histone Deacetylase Inhibitors/chemistry , Histones/metabolism , Humans , Hydroxamic Acids/chemistry , Leukemia, Myeloid, Acute/pathology , Mice , Reactive Oxygen Species/metabolism , Receptors, GABA-A/metabolism , Toxicity Tests, Acute
3.
Neuroscience ; 169(2): 863-73, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20580661

ABSTRACT

The role of voltage-gated sodium channels in the transmission of neuropathic pain is well recognized. For instance, genetic evidence recently indicate that the human Nav1.7 sodium channel subtype plays a crucial role in the ability to perceive pain sensation and may represent an important target for analgesic/anti-hyperalgesic drugs. In this study a newly synthesized tocainide congener, named NeP1, was tested in vitro on recombinant hNav1.4 and hNav1.7 channels using patch-clamp technique and, in vivo, in two rat models of persistent neuropathic pain obtained either by chronic constriction injury of the sciatic nerve or by oxaliplatin treatment. NeP1 efficiently blocked hNav1.4 and hNav1.7 channels in a dose- and use-dependent manner, being by far more potent than tocainide. Importantly, the new compound displayed a remarkable use-dependent effect, which likely resulted from a very high affinity for inactivated compared to closed channels. In both models of neuropathic pain, NeP1 was greatly more potent than tocainide in reverting the reduction of pain threshold in vivo. In oxaliplatin-treated rats, NeP1 even produced greater and more durable anti-hyperalgesia than the reference drug tramadol. In addition, in vivo and in vitro studies suggest a better toxicological and pharmacokinetic profile for NeP1 compared to tocainide. Overall, these results indicate NeP1 as a new promising lead compound for further development in the treatment of chronic pain of neuropathic origin.


Subject(s)
Analgesics/pharmacology , Pain/drug therapy , Peripheral Nervous System Diseases/drug therapy , Sodium Channel Blockers/pharmacology , Sodium Channels/physiology , Tocainide/analogs & derivatives , Tocainide/pharmacology , Analgesics/therapeutic use , Animals , Cell Line , Cell Survival/drug effects , Humans , Hyperalgesia/drug therapy , Male , Muscle Proteins/antagonists & inhibitors , NAV1.4 Voltage-Gated Sodium Channel , NAV1.7 Voltage-Gated Sodium Channel , Patch-Clamp Techniques , Protein Binding , Rats , Rats, Sprague-Dawley , Serum Albumin/metabolism , Sodium Channel Blockers/therapeutic use , Tocainide/therapeutic use
4.
Bioorg Med Chem ; 9(5): 1165-74, 2001 May.
Article in English | MEDLINE | ID: mdl-11377175

ABSTRACT

As a continuation of previous research on anticholinergic drugs derived from 2,2-diphenyl-2-ethylthioacetic acid, several 5,5-diphenyl-5-ethylthio-2-pentynamines (2-11) were synthetised and their antimuscarinic activity on M(1-4) receptor subtypes was evaluated by functional tests and binding experiments. One of the compounds obtained showed unexpected agonistic activity in functional experiments on M(2) receptors. Since the compound carried a phenylpiperazine moiety, other similar compounds (12-17) were prepared and found to be endowed with similar behaviour. These ligands, although possessing the bulky structure characterising muscarinic antagonists, display agonistic activity at M(2) subtypes while, as expected, behaving as antagonists on M(3) and M(4) subtypes. On M(1) subtypes, they show agonistic activity which, however, is not blocked by atropine. The peculiar pharmacological profile of these compounds is of interest for studying muscarinic receptor subtypes.


Subject(s)
Alkynes/pharmacology , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Alkynes/chemical synthesis , Animals , Atropine/pharmacology , Cerebral Cortex/metabolism , Guinea Pigs , Ileum/metabolism , In Vitro Techniques , Lung/metabolism , Male , Myocardium/metabolism , Rabbits , Rats , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Structure-Activity Relationship , Swine , Vas Deferens/metabolism
5.
J Cardiovasc Pharmacol ; 36(5): 584-91, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11065218

ABSTRACT

Blockade of cardiac repolarizing potassium channels by drugs may result in QT-interval prolongation, eventually degenerating into "torsades de pointes," a life-threatening arrhythmia. Lercanidipine (LER) is a recently introduced lipophilic calcium antagonist with no cardiodepressant activity and long-lasting antihypertensive action. Its chemical structure is characterized by the presence of a diphenylpropylaminoalkyl group, which is present in some of the drugs that have been reported to cause QT-interval prolongation. Our previous data demonstrated that LER blocks L-type calcium channels without affecting sodium current; however, no data are available concerning its effects on cardiac potassium channels. Transient outward (I(to)), delayed rectifier (I(K)), background currents, and action potential (AP) profile were measured from patch-clamped ventricular myocytes isolated from rat, guinea pig, or human hearts using enzymatic dissociation procedures. LER did not affect I(K) (and I(Kr)) density and activation curve in guinea pig myocytes; the reversal potential of the background current (I(K1)) and its slope were not changed by the drug. Maximal diastolic potential (MDP) and duration of the AP measured at -60 mV (APD(-60)) were not significantly changed. I(to) density and activation curves measured in rat myocytes were similar in the absence and presence of 1 or 10 microM LER. Finally, the effect of LER was tested in human ventricular myocytes: superfusion with 1 microM LER did not affect MDP and APD(-60). I(to) density and the midpoint of activation and inactivation curves were similar in the absence and presence of LER. In conclusion, our data demonstrate that LER does not affect repolarizing potassium currents and action potential profile recorded from guinea pig, rat, and human ventricular myocytes. It is unlikely that LER could cause QT prolongation in vivo.


Subject(s)
Calcium Channel Blockers/pharmacology , Dihydropyridines/pharmacology , Heart/drug effects , Potassium Channels/drug effects , Action Potentials , Animals , Butylamines/pharmacology , Diphenhydramine/pharmacology , Electric Stimulation , Guinea Pigs , Heart/physiology , Humans , Prenylamine/pharmacology , Rats , Species Specificity , Structure-Activity Relationship
7.
Life Sci ; 65(13): 1381-94, 1999.
Article in English | MEDLINE | ID: mdl-10503957

ABSTRACT

The antinociceptive activity of a 3(2H)-pyridazinone derivative (18a) was investigated in mice. 18a administered at doses which did not change either motor coordination or locomotor activity was able to induce antinociceptive effects in four nociceptive tests, the hot plate test, the tail flick test, the writhing test, and the formalin test. In the hot plate and tail flick test, 18a-induced antinociception was observed both after intraperitoneal administration and after intracerebroventricular injection thus indicating 18a has a central site of action. The pretreatment with the opioid antagonist naloxone, the alpha2-antagonist yohimbine or the GABA(B) antagonist CGP 35348 did not change 18a-induced antinociception in the hot plate test and in the tail flick test. Pretreatment with nicotinic antagonist mecamylamine did not change 18a effects either. A reversion of the 18a effects was observed after pretreatment with the muscarinic antagonists atropine and pirenzepine. Binding experiments revealed that 18a binds to muscarinic receptors, suggesting that 18a antinociception is mediated by central muscarinic receptors. The above findings together with the lack of parasympathomimetic cholinergic side effects indicate useful clinical application for this compound.


Subject(s)
Analgesics, Non-Narcotic/pharmacology , Pyridazines/pharmacology , Animals , Dose-Response Relationship, Drug , Male , Mecamylamine/pharmacology , Mice , Motor Activity/drug effects , Muscarinic Agonists/pharmacology , Naloxone/pharmacology
8.
Neuropharmacology ; 38(3): 339-48, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10219972

ABSTRACT

The effect on memory processes of inactivation of the M1 gene by an antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse passive avoidance test. Mice received a single intracerebroventricular (i.c.v.) injection of M1 aODN (0.3, 1.0 or 2.0 nmol per injection), degenerated ODN (dODN) or vehicle on days 1, 4 and 7. An amnesic effect, comparable to that produced by antimuscarinic drugs, was observed 12, 24, 48 and 72 h after the last i.c.v. aODN injection, whereas dODN and vehicle, used as controls, did not produce any effect. Reduction in the entrance latency to the dark compartment induced by aODN disappeared 7 days after the end of aODN treatment, which indicates the absence of any irreversible damage or toxicity caused by aODN. Quantitative reverse transcription-polymerase chain reaction analysis demonstrated that a decrease in M1 mRNA levels occurred only in the aODN-treated group, being absent in all control groups. Furthermore, a reduction in M1 receptors was observed in the hippocampus of aODN-treated mice. Neither aODN, dODN nor vehicle produced any behavioral impairment of mice. These results indicate that the integrity and functionality of M1 receptors are fundamental in the modulation of memory processes.


Subject(s)
Amnesia/physiopathology , Avoidance Learning/drug effects , Cerebral Ventricles/physiology , Memory/physiology , Oligodeoxyribonucleotides, Antisense/pharmacology , Receptors, Muscarinic/genetics , Amnesia/chemically induced , Animals , Cell Membrane/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Ventricles/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Injections, Intraventricular , Male , Memory/drug effects , Mice , Muscarinic Antagonists/pharmacology , Oligodeoxyribonucleotides, Antisense/administration & dosage , Pirenzepine/analogs & derivatives , Pirenzepine/metabolism , RNA, Messenger/genetics , Reaction Time , Receptor, Muscarinic M1 , Receptors, Muscarinic/physiology , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transcription, Genetic/drug effects
9.
J Eur Acad Dermatol Venereol ; 12(1): 6-10, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10188142

ABSTRACT

Radioligand binding experiments were performed with crude homogenates from normal human skin in order to investigate substance P receptor density. Binding of [3H]substance P ([3H]SP) reached equilibrium after 20 min and was saturable analysis of saturation curves gave a significantly better fit using two-site binding compared to the single-site model. Competition studies employing some selective agonists for NK1, NK2 and NK3 receptors have demonstrated that only the NK1 selective agonist, [Sar9, Met(O2)11]-SP, was a competitor for [3H]SP binding. In addition, the non-hydrolyzable guanosine 5'-0-(3-thiotriphosphate) altered the dissociation of SP from NK1 receptors by increasing the number of low-affinity sites. These data show that in the skin [3H]SP binds to a single population of substance P high-affinity sites, which represent NK1-type receptors.


Subject(s)
Skin/metabolism , Substance P/metabolism , Aged , Binding, Competitive/drug effects , Female , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Humans , Male , Middle Aged , Neurokinin A/analogs & derivatives , Neurokinin A/pharmacology , Neurokinin B/analogs & derivatives , Neurokinin B/pharmacology , Peptide Fragments/pharmacology , Radioligand Assay , Receptors, Neurokinin-1/agonists , Receptors, Neurokinin-1/metabolism , Receptors, Neurokinin-2/agonists , Receptors, Neurokinin-3/agonists , Skin/drug effects , Substance P/analogs & derivatives , Substance P/pharmacology , Tritium
10.
J Cell Physiol ; 178(3): 333-40, 1999 Mar.
Article in English | MEDLINE | ID: mdl-9989779

ABSTRACT

Binding experiments with the specific muscarinic ligand [3H]N-methylscopolamine (3H-NMS) have shown the presence of constitutive muscarinic acetylcholine receptors (mAChR) on Friend murine erythroleukemia cells (MELC). Competition experiments with a panel of specific antagonists indicated that the mAChR were predominantly of the M3 subtype. This was confirmed by the rt-PCR analysis of mRNA levels for M1-M5 AChR. Uninduced MELC expressed approximately 2,100 and 1,200 binding sites per cell of growing and resting populations, respectively. The dissociation constant (K(D)) for 3H-NMS was in the picomolar range. The modulation of mAChR upon induction suggested that MELC growth and maturation might be under control of a cholinergic system since mAChR were markedly decreased or virtually absent in MELC induced to terminal division by dimethyl sulfoxide (DMSO) or hexamethylene bisacetamide (HMBA), respectively. In turn, the number of mAChR on MELC committed to polyploidization by colcemid was either increased over or maintained at the control levels when receptor densities were expressed per cell or surface unit (square micrometers), respectively. Moreover, the muscarinic agonist carbachol was found to inhibit MELC differentiation by decreasing by approximately 35% the amount of benzidine-positive (B+) cells in HMBA-induced cultures and, to a lesser degree, also AChE levels. The carbachol effect on erythroid differentiation was reverted by atropine that was found to restore the original amount of B+ cells, while it reduced acetylcholinesterase (AChE) to levels of approximately 66% of control. Such a selective atropine-mediated inhibition of AChE expression was observed also in HMBA-induced MELC supplemented with the antagonist. These results have suggested that mAChR on MELC are functional and might play a role in modulating the expression of either the erythroid or megakaryocytic traits of these cells.


Subject(s)
Receptors, Muscarinic/physiology , Transcription, Genetic , Acetylcholinesterase/metabolism , Animals , Binding, Competitive , Brain/metabolism , Cell Differentiation , Cell Division , Friend murine leukemia virus , Kinetics , Leukemia, Erythroblastic, Acute , Mice , N-Methylscopolamine/metabolism , Quinuclidinyl Benzilate/pharmacokinetics , RNA, Messenger/genetics , Radioligand Assay , Receptors, Muscarinic/genetics , Receptors, Muscarinic/metabolism , Tritium , Tumor Cells, Cultured
11.
Br J Pharmacol ; 122(7): 1353-60, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9421282

ABSTRACT

1. We used electrophysiological and electron spin resonance (e.s.r.) techniques to study the mechanism of the protective effect of darodipine on rat isolated cardiomyocytes exposed to an exogenous source of oxygen free radicals (OFR). 2. The L-type calcium current (I(Ca,L)), action potential and cell shortening were measured in patch-clamped cells in the whole-cell configuration. I(Ca,L) blockade by darodipine was concentration-dependent, peak current being reduced by 20% with 50 nM and by 58% with 100 nM darodipine. The lowest concentration of darodipine did not affect action potential or twitch profile. 3. Exposure to OFR-generating solution (5 mM dihydroxyfumarate, DHF) caused the appearance of electrophysiological alterations and/or spontaneous activity in 73% of cells (n=26) within 5 min; action potential duration (APD) was prolonged (195+/-16 ms vs 140+/-6 ms in the control) and maximum diastolic potential (MDP) was reduced (-59.5+/-2.6 mV vs -69.8+/-0.8 mV in the control) (P<0.05, n=25). 4. A 2 min pretreatment with 50 nM darodipine significantly reduced the incidence of these arrhythmogenic events following a 5 min exposure to OFR (36% of cells, n=14; P<0.05 vs nonpretreated cells). Pretreatment with darodipine also prevented APD prolongation caused by OFR (137+/-12 ms after DHF vs 117+/-6 ms before DHF n=14, not significant) but not the decrease of MDP (-63.4+/-2.5 mV after DHF vs -70.9+/-1.0 mV before DHF, P<0.05). 5. The e.s.r. spectra obtained from the DHF-DMPO solution in the absence of darodipine demonstrated the presence of two components corresponding to two DMPO adducts. The addition of darodipine (50-500 nM) led to a concentration-dependent decrease in intensity of the signals, the intensity of the DMPO-COO.- adduct being decreased more than that of the DMPO-OH. adduct. 6. Our results demonstrate that darodipine dose-depentently blocks I(Ca,L) in rat isolated cardiomyocytes. Furthermore it exerts protective effects against free-radical-induced electrophysiological alterations independently of its calcium antagonistic properties; this effect is possibly due to trapping of specific radical species.


Subject(s)
Calcium Channel Blockers/pharmacology , Heart/drug effects , Myocardium/cytology , Nifedipine/analogs & derivatives , Animals , Dose-Response Relationship, Drug , Electron Spin Resonance Spectroscopy/methods , Electrophysiology , Free Radicals , Male , Membrane Potentials/drug effects , Nifedipine/pharmacology , Rats , Rats, Wistar , Reactive Oxygen Species/physiology
12.
J Reprod Fertil ; 107(2): 153-60, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8882279

ABSTRACT

The objective of this study was to investigate the contractile response in vitro of uterine and myometrial strips from control and oestrogen-treated guinea-pigs to carbachol. In addition, the muscarinic receptor parameters in subcellular preparations from the myometrium of the same animals were evaluated. Strips of guinea-pig uterus contract in response to carbachol in a concentration dependent manner and the effect of carbachol is independent of the presence of an intact endometrium. However, treatment with oestrogen reduces the response to carbachol, when expressed with respect to the effect of KCl. Measurement of the specific binding of [3H]quinuclidinyl benzylate ([3H]QNB) to myometrial membranes from control and oestradiol-treated immature guinea-pigs showed that oestradiol significantly decreased the number of specific binding sites of [3H]QNB, but did not change the apparent affinity of specific [3H]QNB binding. Moreover, the apparent affinity constants for the different antagonists showed a close similarity to those obtained at muscarinic receptors present in the myometrium from control and oestradiol-treated guinea-pigs.


Subject(s)
Carbachol/pharmacology , Estrogens/pharmacology , Muscarinic Agonists/pharmacology , Receptors, Muscarinic/drug effects , Uterine Contraction/drug effects , Animals , Female , Guinea Pigs , In Vitro Techniques , Myometrium/drug effects , Quinuclidinyl Benzilate/pharmacology , Radioligand Assay
13.
Biochem Biophys Res Commun ; 223(1): 85-90, 1996 Jun 05.
Article in English | MEDLINE | ID: mdl-8660384

ABSTRACT

The carbon centered radicals generated by preincubation of cumene hydroperoxide with rat cardiac membranes dose dependently reduced the Bmax of [3H]nitrendipine binding, while KD was unchanged. The reduction induced by cumene hydroperoxide was prevented by 2,6-di-t-butlyl-4-methyl-phenol. The generation of OH did not influence the [3H]nitrendipine binding; also other oxidative agents (H2O2 and HClO4) did not modify this binding. Therefore the reduction in [3H]nitrendipine binding sites is not attributable to generic oxidative stress but to the formation of carbon centered radicals.


Subject(s)
Benzene Derivatives/pharmacology , Calcium Channels/metabolism , Myocardium/metabolism , Nitrendipine/metabolism , Animals , Butylated Hydroxytoluene/pharmacology , Calcium Channels/drug effects , Calcium Channels, L-Type , Cell Membrane/metabolism , Down-Regulation , Electron Spin Resonance Spectroscopy , Free Radicals , Hydrogen Peroxide/pharmacology , Kinetics , Male , Oxidants/pharmacology , Oxidative Stress , Perchlorates/pharmacology , Rats , Rats, Sprague-Dawley , Sodium Compounds/pharmacology , Superoxides/metabolism
14.
Arch Pharm (Weinheim) ; 329(2): 105-11, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8851474

ABSTRACT

A series of semirigid analogs of compounds 1 and 2, two potent analgesics and cognition enhancers, have been synthesized and tested for antinociceptive activity (hot plate test) and for muscarinic affinity (binding in rat cerebral cortex). They were found to be in general less potent than the reference compounds; only one of them (22) shows a good affinity for the muscarinic receptor and an antinociceptive efficacy comparable with those of the reference compounds. At a dose of 30 mg/kg 22 is also able to reverse the amnesic effect of dicyclomine. Since the analgesic effect of these compounds is affected by the 5-HT4 antagonist SDZ 205557, the possible role of this receptor is discussed.


Subject(s)
Analgesics/pharmacology , Cognition/drug effects , Tropanes/pharmacology , Analgesics/chemical synthesis , Animals , Male , Mice , Rats , Receptors, Muscarinic/metabolism , Serotonin Antagonists/pharmacology , Structure-Activity Relationship
15.
Farmaco ; 49(5): 305-12, 1994 May.
Article in English | MEDLINE | ID: mdl-8080612

ABSTRACT

In order to develop compounds which may be useful in the treatment of memory and cognitive disorders we have synthesized and tested some 1,3-oxathiolane derivatives bearing an amidine function instead of the classical ammonium head, with the aim of improving brain penetration. The compounds were tested on peripheral and central models of muscarinic receptors. The results show that, unlike for other series of muscarinic ligands, this modification results in the reduced potency of antagonists, shifts the activity of agonists toward weak antagonism and does not introduce any noteworthy subtype selectivity.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Thiophenes , Amidines/chemical synthesis , Amidines/pharmacology , Animals , Blood-Brain Barrier , Cations , Guinea Pigs , Heterocyclic Compounds/pharmacology , In Vitro Techniques , Ligands , Muscle, Smooth/drug effects , Rabbits , Receptors, Muscarinic/drug effects
16.
Arzneimittelforschung ; 43(8): 913-8, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8216452

ABSTRACT

A series of aryl tropanyl esters and amides related to 1H-indole-3-carboxylic acid endo 8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (ICS 205930, CAS 89565-68-4) were synthesized and evaluated for antinociceptive activity using the hot-plate test. Of these, the benzofurane-3-carboxylic ester of tropine (1) was found powerfully to increase the pain threshold, with a cholinergic mechanism of action. Despite the structural similarity with ICS 205930, the analgesia induced by 1 seems not to be due to 5-HT3 receptor interaction, and there is evidence of involvement of the central 5-HT4 receptor.


Subject(s)
Analgesics/chemical synthesis , Indoles/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Tropanes/chemical synthesis , Analgesics/pharmacology , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , In Vitro Techniques , Indoles/pharmacology , Male , Membranes/metabolism , Mice , Naloxone/pharmacology , Pain Measurement/drug effects , Rats , Rats, Wistar , Receptors, Muscarinic/drug effects , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Tropanes/pharmacology , Tropisetron
17.
Br J Pharmacol ; 109(4): 1038-45, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8401916

ABSTRACT

1. In rat isolated vas deferens the new compound 2,6-dibutylbenzylamine (B25) evoked a series of repeating rhythmic contractions. Concentration-response curves constructed for this effect were bell-shaped, indicating a biphasic effect for this compound. By contrast, B25 depressed heart contractility without any visible positive inotropic or chronotropic activity. 2. Experiments with tetrodotoxin, reserpine, capsaicin, alpha-adrenoceptor blocking compounds and other agents permit us to exclude a release of neuromediators or a direct stimulation of post-synaptic receptors to account for the rhythmic effect of B25 in the rat vas deferens. 3. In the same tissue, the increase in 45Ca2+ uptake, the voltage-dependency as well as the dependence of the B25-induced rhythmic activity upon the external calcium concentration indicate a direct activation of voltage-sensitive calcium channels (VSCC). 4. Verapamil paradoxically stimulated the rhythmic effect of B25 in the rat vas deferens. La3+ was inactive while nifedipine was a weak inhibitor. By contrast Ni2+ and Mn2+ ions were good inhibitors (IC50 < 10(-4) M), suggesting that a possible opening of T-type VSCC underlies rhythmic effect of B25. 5. In radioligand binding studies competition experiments with [3H]-nitrendipine indicated that only at high concentrations was B25 able to interact with dihydropyridine-sensitive binding sites of heart and vas deferens smooth muscle. 6. B25 (3-30 microM) counteracted the inhibitory effects of omega-conotoxin GVIA in field-stimulated rat vas deferens.


Subject(s)
Benzylamines/pharmacology , Calcium/physiology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth/drug effects , Myocardial Contraction/drug effects , Animals , Binding, Competitive/drug effects , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Calcium Radioisotopes , Electric Stimulation , Female , Guinea Pigs , Heart/drug effects , Heart Rate/drug effects , Ileum/drug effects , In Vitro Techniques , Male , Membranes/drug effects , Membranes/metabolism , Nitrendipine/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Vas Deferens/drug effects
18.
Chirality ; 5(3): 135-42, 1993.
Article in English | MEDLINE | ID: mdl-8338723

ABSTRACT

The antiarrhythmic drug tocainide (5a) and some related chiral alpha-amino and alpha-imino anilides (5b-e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of tocainide is due only to its (-)-(R)-enantiomer. Benzyl replacement for methyl group at the stereogenic centre of tocainide causes loss of activity while both enantiomers of the alpha-iminoxilidide 5e and of the strictly related tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [3H] quinuclidinyl benzilate ([3H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (-)-(R)-tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action.


Subject(s)
Analgesics/pharmacology , Central Nervous System/drug effects , Tocainide/analogs & derivatives , Tocainide/pharmacology , Animals , Atropine/pharmacology , Brain Chemistry/drug effects , Chemical Phenomena , Chemistry, Physical , Hemicholinium 3/pharmacology , In Vitro Techniques , Injections, Intraventricular , Injections, Subcutaneous , Male , Mice , Pain Threshold/drug effects , Postural Balance/drug effects , Quinuclidinyl Benzilate , Rats , Rats, Sprague-Dawley , Stereoisomerism , Tocainide/administration & dosage
19.
Pharmacol Res ; 26(2): 151-9, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1329063

ABSTRACT

The incubation of xanthine-oxidase (XOD) with rat cardiac membranes induced the formation of free radicals; they were identified by electron spin resonance spectroscopy (ESR) studies using 0.1 M 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) for spin-trapping. The following DMPO adducts were measured: DMPO-OH, which was produced during the first minute of incubation, DMPO-R radicals, which were present after 4 min of incubation and where the signal intensity remained constant for at least 20 min. The binding studies performed after 15 min incubation showed that XOD (1-50 mU) dose dependently reduced 3H-nitrendipine binding. This reduction was caused by a decrease in the density of binding sites while the affinity remained unchanged. These results suggest that ethoxy radical formation may be an important step in the regulation of L type calcium channels.


Subject(s)
Myocardium/metabolism , Nitrendipine/metabolism , Xanthine Oxidase/pharmacology , Animals , Binding Sites/drug effects , Cell Membrane/drug effects , Cell Membrane/metabolism , Cyclic N-Oxides/metabolism , Electron Spin Resonance Spectroscopy , Free Radicals/pharmacology , Gas Chromatography-Mass Spectrometry , Heart/drug effects , Ligands , Male , Rats , Rats, Sprague-Dawley , Spin Labels
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