Biomedical subjects

G Bietti

Publications and source records attributed to G Bietti.

13 recordsLinked to original sources

PubMed1995

BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex.

In the search for antidepressant agents with a rapid onset of action, we have found that compound BIMT 17 (1-[2-[4-(3-trifluoromethylphenyl)piperazin-1- yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity for cerebral cortical 5-HT1A (pKi = 7.72) and 5-HT2A (pKi = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT2C. BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC50 = 6.09) and in the hippocampus (pEC50 = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pKi = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT1A receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 (1-[2-(2-thenoylamino)ethyl]- 4[1-(7-methoxynaphtyl)]-piperazine), claimed to be 5-HT1A receptor agonists, did not reduce forskolin-stimulated cAMP formation in the cerebral cortex. On the basis of these data, it was concluded that BIMT 17 was the only compound that behaved as a full agonist with respect to the cAMP response in the cortex, while exerting concurrent agonism at 5-HT1A receptors and antagonism at 5-HT2A receptors. These characteristics might explain the peculiar behavior of BIMT 17 in mimicking the inhibitory action of 5-HT on the basal firing rate of the cortical neurons (see accompanying paper).

Animals↗

PubMed1995

BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist, directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex.

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT1A receptor agonist/5-HT2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1-10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1-1000 micrograms/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4-[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1-10 micrograms/kg and 0.1-3 micrograms/kg i.v. respectively, and reduced it at high doses, 30-300 micrograms/kg and 10-30 micrograms/kg i.v., respectively. The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OH-DPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

Substituent effect on the stereochemistry of H2-receptor antagonists of the phenylformamidine series. A conformation-dependent mode of interaction with the H2 receptor.

The influence of alkyl substitution on the stereoisomerism of the formamidine cation (E,E vs E,Z) of several N-substituted (imidazolylphenyl)formamidines (1-10) was investigated. As (imidazolylphenyl)formamidines having alkyl substituents of more than three carbon atoms bind to H2-receptor preparations in a pseudoirreversible mode causing unsurmountable antagonism, the four isomeric butylformamidines (5-7 and 9) having comparable lipophilic character but different E,E/E,Z composition were investigated in H2-receptor assays to determine quantitatively any difference in their pseudoirreversible inhibitory pattern. It was found that the geometry of the formamidine cation is affected by the steric bulk of the substituent on the formamidine nitrogen. A relationship between the percentage of the E,E conformation of the formamidine cation and degree of pseudoirreversible antagonism was also found. The present studies support the hypothesis that bidentate hydrogen bonding plays an important role in the interaction of (imidazolylphenyl)formamidines with the H2 receptor.

Amidines↗

PubMed1990

Irreversible H2-antagonism of the four isomeric butyl analogues of mifentidine.

It has been hypothesized that bidentate hydrogen bonding plays an important role in the interaction of imidazolylphenylformamidines with the H2-receptor. The present study, in which the degree of pseudo-irreversible H2-antagonism of the four isomeric butyl substituted mifentidine analogues was determined on the spontaneously beating right atrium of the male guinea-pig, lends further support to this hypothesis. In solution the EE/EZ ratio is different for the four isomeric butylated mifentidine analogues. The rank order of the percentage of E,E conformation, which favors a bidentate interaction, of the formamidine moiety parallels the rank order of pseudo-irreversible H2-antagonism.

Animals↗

PubMed1985

Conformational studies of two histamine H2-receptor antagonistic phenylformamidines: mifentidine and its guanidinothiazole analogue DA 4643.

Two histamine H2-receptor antagonists of the phenylformamidine type, mifentidine (N-isopropyl-N'-(4-1H-imidazol-4-yl-phenyl) formamidine dihydrochloride; I) and DA 4643 (N-methyl-N'-(3-(2-guanidinothiazol-4-yl)-phenyl) formamidine dihydrochloride; II), have been investigated by experimental physico-chemical studies and theoretical conformational analysis. PKa determinations on the two molecules I and II show that these substances exist at physiological pH (7.4) predominantly as their monoprotonated forms at the formamidine moiety. Semiempirical quantum mechanical (MNDO, CNDO/2) and molecular mechanics (MMPI) calculations show a preference of the nearly planar conformations for I and of different low energy rotamers for II. The energy of these conformers is a function of two important torsion angles, one around the bond joining the imidazole, or the guanidinothiazole, and the phenyl ring and the other around the bond joining the phenyl ring and the formamidinium cation. When the distances between crucial parts present in I and II are considered, it results that the relatively higher flexibility of II allows accommodation of amidine pairs present in the latter at a distance similar to that found for correspondent pairs in the conformationally more restricted I. Conformational aspects of I and II are discussed with reference to a recently described conformation of cimetidine determined by X-ray method. A hypothesis of binding of H2-receptor antagonists of the phenylformamidine type is advanced with reference to electrostatic potential maps calculated for crucial part structures of I, II and cimetidine. The present work supports the hypothesis that both mifentidine and DA 4643 interact with the histamine H2-receptor at the same site, utilizing in the binding process the same, or closely similar, receptor structural features.

Chemical Phenomena↗

PubMed1976

Possibility of isoproterenol therapy with soft contact lenses: ocular hypotension without systemic effects.

An experimental investigation performed in the rabbit pointed out the possibility of administering isoproterenol at low concentrations with the aid of soft contact lenses presoaked in 0.2% isoproterenol for 60 to 120 minutes. A reduction in intraocular pressure ranging from 23% to 32% was observed in 21 out of 24 glaucomatous patients. Duration of hypotension in 50% of eyes treated was more than 8 hours. Thus, a therapeutic effect was obtained with a concentration (0.2%) approximately 50 times lower than that previously employed clinically (2.4%). No systemic side effects, such as arterial hypotension and increase in heart rate, were noted.

Animals↗

PubMed1975

Acetazolamide, metabolic acidosis, and intraocular pressure.

In order to investigate whether or not there is a causal relationship between the metabolic acidosis and the ocular hypotension induced by acetazolamide, we undertook to correlate over a period of time the blood-acidifying and ocular-hypotonizing effects of administering the lowest intravenous effective dose of acetazolamide; to treat the metabolic acidosis induced by acetazolamide by means of the intravenous introduction of bases, and pulmonary hyperventilation (respiratory alkalosis); to evaluate the effects on the intraocular pressure (IOP) by neutralizing the acetazolamide-induced metabolic acidosis by means of a continuous infusion of sodium bicarbonate; to determine the relationship between the metabolic acidosis induced by blood-acidifying agents, which do not inhibit carbonic anhydrase, and the IOP; and to determine the changes in the acid-base status of the aqueous humor induced by acetazolamide and other blood-acidifying drugs. We found that the hypertonic buffering solution of sodium bicarbonate could reduce the IOP by itself through an osmotic mechanism. On the basis of our results, we believe that a causal relationship exists between the metabolic acidosis induced by acetazolamide, and by other drugs that have a blood-acidifying effect as the result of other mechanisms, and ocular hypotension, bothin the animal and in the glaucomatous patient.

Acetazolamide↗

PubMed1972