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Biomedical subjects

F Gualtieri

Publications and source records attributed to F Gualtieri.

At least 37 records · Page 2Linked to original sources
PubMed1998

Memory facilitation and stimulation of endogenous nerve growth factor synthesis by the acetylcholine releaser PG-9.

The effects of PG-9 (3alpha-tropyl 2-(p-bromophenyl)propionate), the acetylcholine releaser, on memory processes and nerve growth factor (NGF) synthesis were evaluated. In the mouse passive-avoidance test, PG-9 (10-30 mg/kg, i.p.), administered 20 min before the training session, prevented amnesia induced by both the non selective antimuscarinic drug scopolamine and the M1-selective antagonist S-(-)-ET-126. In the same experimental conditions, PG-9 (5-20 microg per mouse, i.c.v.) was also able to prevent antimuscarine-induced amnesia, demonstrating a central localization of the activity. At the highest effective doses, PG-9 did not produce any collateral symptoms as revealed by the Irwin test, and it did not modify spontaneous motility and inspection activity, as revealed by the hole-board test. PG-9 was also able to increase the amount of NGF secreted in vitro by astrocytes in a dose-dependent manner. The maximal NGF contents obtained by PG-9 were 17.6-fold of the control value. During culture, no morphological changes were found at effective concentrations of PG-9. The current work indicates the ability of PG-9 to induce beneficial effects on cognitive processes and stimulate activity of NGF synthesis in astroglial cells. Therefore, PG-9 could represent a potential useful drug able to improve the function of impaired cognitive processes.

Acetylcholine↗
PubMed1998

Antinociceptive and antiamnesic properties of the presynaptic cholinergic amplifier PG-9.

The antinociceptive effect of 3 alpha-tropyl 2-(p-bromophenyl)propionate [(+/-)-PG-9] (10-40 mg kg-1 s.c.; 30-60 mg kg-1 p.o.; 10-30 mg kg-1 i.v.; 10-30 micrograms/mouse i.c.v.) was examined in mice, rats and guinea pigs by use of the hot-plate, abdominal-constriction, tail-flick and paw-pressure tests. (+/-)-PG-9 antinociception peaked 15 min after injection and then slowly diminished. The antinociception produced by (+/-)-PG-9 was prevented by the unselective muscarinic antagonist atropine, the M1-selective antagonists pirenzepine and dicyclomine and the acetylcholine depletor hemicholinium-3, but not by the opioid antagonist naloxone, the gamma-aminobutyric acidB antagonist 3-aminopropyl-diethoxy-methyl-phosphinic acid, the H3 agonist R-(alpha)-methylhistamine, the D2 antagonist quinpirole, the 5-hydroxytryptamine4 antagonist 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, the 5-hydroxytryptamin1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide and the polyamines depletor reserpine. Based on these data, it can be postulated that (+/-)-PG-9 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. (+/-)-PG-9 (10-40 mg kg-1 i.p.) was able to prevent amnesia induced by scopolamine (1 mg kg-1 i.p.) and dicyclomine (2 mg kg-1 i.p.) in the mouse passive-avoidance test. Affinity profiles of (+/-)-PG-9 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M1, guinea pig atrium for M2, guinea pig ileum for M3 and immature guinea pig uterus for putative M4), have shown an M4/M1 selectivity ratio of 10.2 that might be responsible for the antinociception and the anti-amnesic effect induced by (+/-)-PG-9 through an increase in acetylcholine extracellular levels. In the antinociceptive and antiamnesic dose range, (+/-)-PG-9 did not impair mouse performance evaluated by the rota-rod test and Animex apparatus.

Amnesia↗
PubMed1997

SAR studies on the potent and selective muscarinic antagonist 2-ethylthio-2,2-diphenylacetic acid N,N-diethylaminoethyl ester.

Molecular modification of the potent and selective muscarinic antagonist 2-ethylthio-2,2-diphenylacetic acid N,N-diethylaminoethyl ester was performed in order to identify M2 selective antagonists able to cross the blood brain barrier and potentially useful in the treatment of Alzheimer's disease. Modifications included substitution or hydrogenation of one of the phenyl rings as well as their incorporation in a tricyclic system. In general the changes introduced were detrimental for both affinity and selectivity. Only a modest M2 selectivity is present in some compounds that, on the other hand, carry a quaternary ammonium group which precludes their penetration into the brain.

Analgesics↗
PubMed1997

Antinociception induced by SM 32 depends on a central cholinergic mechanism.

The antinociceptive effect of SM 32 was examined in mice by using the hot-plate (10-40 mg kg(-1) i.p; 3-30 microg per mouse i.c.v.) and abdominal constriction (10-30 mg kg(-1) i.p) tests. In the antinociceptive dose-range, SM 32 did not impair mouse spontaneous motility and motor coordination evaluated respectively by the Animex and rota-rod tests. The increase in the pain threshold produced by SM 32 was prevented by dicyclomine, pirenzepine and hemicholinium-3 but not by naloxone and CGP 35348. In vitro experiments showed that the SM 32 amplified electrically- and nicotine-evoked guinea-pig ileum contractions. On the basis of the above data, it can be postulated that SM 32 exerts its antinociceptive effect through a potentiation of central cholinergic transmission.

Analgesics↗
PubMed1997

Antiamnesic activity of metoclopramide, cisapride and SR-17 in the mouse passive avoidance test.

The effects of the administration of metoclopramide, cisapride and SR-17 on memory processes were evaluated in the mouse passive avoidance test. The administration of dicyclomine (0.1-3 mg kg-1 i.p.), immediately after termination of the training session, produced a dose-dependent amnesic effect. Metoclopramide (1-5 mg kg-1 i.p.), cisapride (0.5-2 mg kg-1 i.p.) and SR-17 (1-10 mg kg-1 i.p.), administered 20 min before the training session, prevented dicyclomine-induced amnesia. In the same experimental conditions piracetam (30 mg kg-1 i.p.), physostigmine (0.2 mg kg-1 i.p.) and CGP 35348 (100 mg kg-1 i.p.) prevented dicyclomine amnesia. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota-rod test, nor did they modify spontaneous motility, as revealed by the Animex test. These results suggest that metoclopramide, cisapride and SR-17 play an important role in the modulation of memory processes. On these bases, these compounds could be useful in the treatment of cognitive deficits.

Amnesia↗
PubMed1997

In vitro characterization of a novel, potent and selective M3 antagonist.

The pharmacological profile of the competitive muscarinic antagonist (2S, 3'R) 3-quinuclidinyl tropate, abbreviated (-)-2a, was evaluated on rabbit vas deferens (M1/M4-like; pA2=9.10), guinea-pig left atrium (M2; pA2=9.30), guinea-pig ileum (M3; pA2=10.33) and guinea-pig uterus (M4 putative; pA2=9.70) muscarinic receptors and on the five subtypes of muscarinic receptors expressed individually in CHO-K1 cells. The drug shows an affinity for the M3 receptor subtype at least 10-fold higher than 4-DAMP, p-HHSiD and zamifenacin, used as reference drugs. These results suggest (-)-2a as a novel, potent and selective M3 antagonist that may have therapeutic potential in the treatment of conditions associated with increased smooth muscle contractility.

Animals↗
PubMed1997

Stereoselective increase in cholinergic transmission by R-(+)-hyoscyamine.

R-(+)-hyoscyamine, the dextro enantiomer of atropine, has been shown to amplify cholinergic transmission. R-(+)-hyoscyamine, unlike S-(-)-hyoscyamine, was able to increase acetylcholine release both in vitro and in vivo at a range of concentrations (10(-14) to 10(-12) M) and doses (5 microg/kg i.p.) which were inadequate for blocking muscarinic receptors. The increase over control values in ACh release was 15.9 +/- 2.1% in in vitro experiments performed in rat phrenic nerve-hemidiaphragm preparations (n = 6), and 63.3 + 16.3% in cortical microdialysis performed in free-moving rats (n = 5). The maximum ACh release was reached 60 min after R-(+)-hyoscyamine administration in in vivo experiments. At the same doses and concentrations, R-(+)-hyoscyamine was also able to elicit: antinociception of a cholinergic type (55.6-112.7% depending on the test used); complete prevention of scopolamine- and dicyclomine-induced amnesia; potentiation of muscular contractions electrically evoked in isolated guinea-pig ileum (16.7 +/- 3.6%) and in rat phrenic nerve-hemidiaphragm (19.9 +/- 3.2%) preparations. Antinociception was performed using the hot-plate and acetic acid abdominal constriction tests in mice, and the paw pressure test in rats, while prevention of induced amnesia was evaluated in mice using the passive-avoidance test. The respective affinities (pA2) for R-(+)- and S-(-)-hyoscyamine vs M1 (rabbit vas deferens), M2 (rat atrium) and M3 (rat ileum) receptor subtypes were as follows: 7.05 +/- 0.05/9.33 +/- 0.03 for M1; 7.25 +/- 0.04/8.95 +/- 0.01 for M2; 6.88 +/- 0.05/9.04 +/- 0.03 for M3. The respective pKi values for R-(+)- and S-(-)-hyoscyamine vs the five human muscarinic receptor subtypes expressed in Chinese hamster oocytes (CHO-K1) were as follows: 8.21 +/- 0.07/9.48 +/- 0.18 for m1; 7.89 +/- 0.06/9.45 +/- 0.31 for m2; 8.06 +/- 0.18/9.30 +/- 0.19 for m3; 8.35 +/- 0.11/9.55 +/- 0.13 for m4; 8.17 +/- 0.08/9.24 +/- 0.30 for m5.

Animals↗
PubMed1997

Antinociceptive profile of 3-alpha-tropanyl 2-(4-Cl-phenoxy)butyrate (SM-21) [corrected]: a novel analgesic with a presynaptic cholinergic mechanism of action.

The antinociceptive effect of (+/-)-3-alpha-tropanyl 2-(4-Cl-phenoxy)butyrate [corrected] (SM-21) (10-40 mg kg(-1) s.c., 10-30 mg kg(-1) i.p., 20-60 mg kg(-1) p.o., 3-20 mg kg(-1) i.v. and 5-20 microg per mouse i.c.v.) was examined in rodents and guinea pigs by using the hot-plate, abdominal constriction, tail-flick and paw-pressure tests. The antinociception produced by (+/-)-SM-21 was prevented by atropine, pirenzepine and hemicholinium-3 but not by quinpirole, R-(alpha)-methylhistamine, [1-[2(methylsufonyl)amino]ethyl]-4-piperidinyl]methyl-5-floro++ +-2-methoxy-1H-indole-3-carboxylate hydrochloride, N6-cyclopentyladenosine, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide, naloxone, 3-aminopropyl-diethoxy-methyl-phosphinic acid or reserpine. On the basis of the above data, it can be postulated that (+/-)-SM-21 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. Affinity profiles of (+/-)-SM-21 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M1, guinea pig atrium for M2, guinea pig ileum for M3 and immature guinea pig uterus for putative M4) have shown a selectivity ratio M2/M1 of 4.6 that, although very low, might be responsible for the antinociception induced by (+/-)-SM-21 through an increase in ACh extracellular levels. In the antinociceptive dose range, (+/-)-SM-21 did not impair mouse performance evaluated by the rota-rod and hole-board tests.

Analgesics↗
PubMed1996

Synthesis and enantioselectivity of the enantiomers of PG9 and SM21, new potent analgesic and cognition-enhancing drugs.

The enantiomers of two alpha-tropanyl esters, SM21 (1) and PG9 (2), derived from (+)-R-hyoscyamine, that act by increasing the central cholinergic tone, were obtained by esterification after resolution of the corresponding racemic acids [(-)-S-1, (-)-R-2 and (+)-S-2] and by stereospecific synthesis [(+)-R-1]. Their analgesic and cognition-enhancing activities were tested in mice and their ACh-releasing properties determined on rat parietal cortex. These compounds show enantioselectivity in analgesic and cognition-enhancing tests on mice, the eutomers being the isomers which possess the same spatial arrangement of the groups on the chiral atom as (+)-R hyoscyamine [(+)-R-SM21, (+)-S-PG9]. The ACh-releasing effect of the enantiomers of SM21 in rats is in agreement with the results in mice, while PG9 enantiomers do not show any appreciable enantioselectivity in this test. On the basis of the different effects of the 5-HT4 antagonist SDZ 205557 on analgesia induced by the enantiomers of 1 and 2 and by (+)-R-hyoscyamine and the alpha-tropanyl ester of 2-phenylpropionic acid 3, a mechanism of action is proposed for this class of compounds.

Acetylcholine↗
PubMed1996

Reduced flexibility analogs of analgesic and cognition enhancing alpha-tropanyl esters.

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.

Analgesics↗
PubMed1996

S-(-)-ET 126: a potent and selective M1 antagonist in vitro and in vivo.

The pharmacological profile of the competitive muscarinic antagonist S-(-)-alpha-(hydroxymethyl)benzeneacetic acid 1-methyl-4-piperidinyl ester (S-(-)-ET 126) was evaluated on M1 (rabbit vas deferens; pA2=8.99), M2 (rat left atrium; pA2=8.21) and M3 (rat ileum; pA2=6.84) muscarinic receptors in comparison with pirenzepine. The drug shows a subtype selectivity (M1/M2=8; M1/M3=178; M2/M3=22) that proposes it as a useful pharmacological tool for receptor studies. S-(-)-ET 126, like pirenzepine, prevents the antinociception induced by M1 agonists (McN-A-343 and AF-102B). Unlike pirenzepine and spirotramine, the compound is able to cross the blood brain barrier which makes it useful for in vivo investigations.

Acetylcholine↗
PubMed1996

Central cholinergic antinociception induced by 5HT4 agonists: BIMU 1 and BIMU 8.

The antinociceptive effect of two 5-HT4 agonists, BIMU 1 and BIMU 8, were examined in mice and rats by using the hot-plate, abdominal constriction and paw-pressure tests. In both species, BIMU 1 (10-20 mg kg-1 s.c. and 40-60 mg kg-1 p.o. in mice; 20 mg kg-1 i.p. in rats) and BIMU 8 (20-30 mg kg-1 s.c. and 60 mg kg-1 p.o. in mice; 20 mg kg-1 i.p. in rats), produced significant antinociception which was prevented by atropine (5 mg kg-1 i.p.), hemicholinium-3 (1 microgram per mouse i.c.v.), SDZ 205-557 (10 mg kg-1 i.p.), GR 125487 (20 mg kg-1 i.p.) but not by naloxone (1 mg kg-1 i.p.), CGP 35348 (100 mg kg-1 i.p.) and reserpine (2 mg kg-1 i.p.). Moreover, BIMU 1 and BIMU 8 increase of pain threshold, is abolished by nucleus basalis magnocellularis (NBM) lesions in rats. SDZ 205-557 and GR 125487 which totally antagonized BIMU 1 and BIMU 8 antinociception did not modify morphine (7 mg kg-1 s.c.) or baclofen (4 mg kg-1 s.c.) antinociception. Intracerebroventricular injection in mice of BIMU 1 (3 micrograms per mouse) and BIMU 8 (10 micrograms per mouse), doses which were largely ineffective by parenteral routes, induces an antinociception whose intensity equaled that obtainable s.c., i.p. or p.o. In the antinociceptive dose-range, neither 5HT4 agonist impaired mice motor coordination evaluated by rota-rod test. On the basis of the above data, it can be postulated that BIMU 1 and BIMU 8 exerted an antinociceptive effect mediated by a central amplification of cholinergic transmission.

4-Aminobenzoic Acid↗
PubMed1995

Structural dependence of the allosteric interaction of semi-rigid verapamil analogues with dihydropyridine-binding in kitten heart.

Structural determinants of the allosteric interaction of semi-rigid verapamil analogues with dihydropyridine binding were investigated in kitten heart using [3H](+)-isradipine as radioligand. Chemical variations were performed in the alkyl chain of verapamil and include introduction of unsaturation (double or triple bonds) or the insertion of cyclohexyl moieties. Introduction of unsaturation generally reduces the allosteric interaction in the case of 'double bond'-and abolishes it in the case of 'triple bond'-derivatives. Also the introduction of cyclohexyl moieties diminishes the potency of allosteric interaction: derivatives with the phenylethylamino side chain in an equatorial position exhibit the allosteric interaction, while it is lacking in derivatives with the basic side chain in axial position. Thus, the reduced conformational flexibility of the new verapamil congeners reduces or abolishes their ability to allosterically interfere with dihydropyridine binding. A molecular interpretation was approached by molecular modelling studies. The strategy was to find low energy conformations common to the active congeners, but not shared by the inactive ones. Structural features discriminating allosterically active and inactive congeners comprise: 1) the position of the nitrogen, 2) the volume occupied by the N-methyl groups, 3) the direction of the N-H bond and 4) the position of the phenyl ring in the basic side chain.

Allosteric Site↗
PubMed1995

Reversal of multidrug resistance by verapamil analogues.

The basic distinguishing feature of multidrug resistant (MDR) cells is a decrease in steady-state drug levels as compared to drug-sensitive controls. It is well-known that verapamil increases the sensitivity of MDR cells to drugs, thus reverting drug resistance. A limiting factor for its clinical use is the pronounced cardiovascular effects of the calcium channel antagonist which occur at the high plasma concentrations required to block P-glycoprotein transport efficiently. From a clinical point of view, it is important to find verapamil derivatives with low calcium channel blocking activity and high reverting activity. This was the aim of the present study. In this context we have investigated the ability of 20 verapamil analogues with restricted molecular flexibility to increase cellular accumulation of anticancer drugs and overcome resistance, and their inotropic, chronotropic, and slow calcium channel antagonistic activity. In this study an anthracycline derivative 4'-O-tetrahydropyranyl adriamycin, and an erythroleukaemia K562 cell line were used. Three of the 20 derivatives checked were completely devoid of calcium channel blocking activity while exhibiting MDR reverting ability comparable to that of verapamil. These derivatives could be useful for the treatment of MDR in cancer patients and for the design and development of other verapamil derivatives.

Calcium↗
PubMed1995

Cardioselective derivatives of 2,2-diphenyl-2-ethylthioacetate do not discriminate between m2 and m3 muscarinic receptors expressed in CHO cells.

Characteristics of interaction of two derivatives of 2,2-diphenyl-2-ethylthioacetate with muscarinic receptors were studied in Chinese hamster ovary (CHO) cells stably transfected with the genes of human m2 and m3 muscarinic receptors. Data from radioligand-receptor binding assays and measurements of m2 receptor-inhibited cyclic AMP formation and m3 receptor-stimulated phosphoinositide (PI) hydrolysis showed that this new series of muscarinic receptor antagonists exhibited a middle range of affinities in binding to muscarinic receptors (Ki = 0.2-0.7 mumol/l), without being able to discriminate between m2 and m3 receptors. They completely displaced [3H]N-methylscopolamine ([3H]NMS) binding at equilibrium and inhibited receptor-mediated increase in PI turnover in m3 CHO cells and decrease in cyclic AMP synthesis in m2 CHO cells in an apparent competitive manner. However, higher concentrations of the compounds (> 10 mumol/l) decelerated the kinetics of atropine-induced dissociation of [3H]NMS at m2 and m3 receptors, indicating an allosteric interaction. Collectively, our results demonstrate that these derivatives of 2,2-diphenyl-2-ethylthioacetate display a mixed mechanism of interaction with muscarinic receptors, being competitive at low concentrations and allosteric at higher concentrations. In contrast to previous reports of a significantly higher affinity at cardiac M2 as compared to ileal M3 receptor, these compounds do not exhibit such selectivity when the two receptor subtypes are expressed in the same type of cells.

Animals↗
PubMed1995

Analgesic, antimuscarinic activity and enantioselectivity of the four isomers of 3-quinuclidinyl tropate as compared with the enantiomers of hyoscyamine.

The four stereoisomers of 3-quinuclidinyl tropate (2) were synthesized and their absolute configuration established. The analgesic activity of the four isomers on the hot-plate test and their muscarinic antagonism on rabbit vas deferens (M1), guinea-pig heart (Force, M2) and ileum (M3) and on the muscarinic receptors present in immature guinea-pig uterus were evaluated. The results were compared with those of the enantiomers of hyoscyamine (1). No apparent correlation was found between the analgesic activity and antimuscarinic activity on M1, M2 and M3 receptors, whereas striking differences exist between the affinity values of the analgesic enantiomer of hyoscyamine (R-(+)-1) and those of the inactive isomers of 2 on the muscarinic receptor present in immature guinea pig uterus. Molecular Modelling studies have shown that the only difference between 1 and 2 lies in the volumes occupied by the basic part of the molecules.

Analgesics↗
PubMed1994

Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters.

Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((+/-)-19, PG9) also has remarkable cognition-enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.

Acetylcholine↗