RESUMEN
Several N-(indol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. From these compounds, the N-[(5-chloro-, 5-bromo-, or 5-nitroindol-3-yl)glyoxylyl]glycine or -alanine esters were clearly the most potent, while the 5-methoxy analogues were considerably less active. Moreover, esters were more active than the corresponding acids. It is concluded that the affinity of these derivatives for the benzodiazepine receptor is profoundly dependent on amino acid molecular size, as well as the hydrophobic and electronic properties of the compounds.
Asunto(s)
Aminoácidos/farmacología , Indoles/farmacología , Receptores de GABA-A/efectos de los fármacos , Alanina/análogos & derivados , Alanina/síntesis química , Alanina/farmacología , Aminoácidos/síntesis química , Animales , Encéfalo/metabolismo , Bovinos , Flunitrazepam/metabolismo , Glicina/análogos & derivados , Glicina/síntesis química , Glicina/farmacología , Técnicas In Vitro , Indoles/síntesis química , Receptores de GABA-A/metabolismo , Relación Estructura-ActividadRESUMEN
Several optically active N-(indol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. IC50 values were measured and revealed that the D form of the amino acid moiety of the compounds was more potent than both the L form and racemic form, suggesting a key role of the amino acid stereochemistry on the affinity to the benzodiazepine receptors. GABA ratio and proconvulsant/convulsant data reported for the most active compounds reveal they behave as inverse agonists at the benzodiazepine receptor.
Asunto(s)
Aminoácidos/farmacología , Indoles/farmacología , Receptores de GABA-A/efectos de los fármacos , Aminoácidos/síntesis química , Animales , Bovinos , Corteza Cerebral/metabolismo , Fenómenos Químicos , Química , Indoles/síntesis química , Conformación Molecular , Receptores de GABA-A/metabolismo , EstereoisomerismoRESUMEN
Radioligand binding assays using bovine cortical membrane preparations and biochemical in vitro studies revealed that various 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one (ATBI) derivatives, previously reported by us as ligands of the central benzodiazepine receptor (BzR) (Primofiore, G.; et al. J. Med. Chem. 2000, 43, 96-102), behaved as antagonists at the A1 adenosine receptor (A1AR). Alkylation of the nitrogen at position 10 of the triazinobenzimidazole nucleus conferred selectivity for the A1AR vs the BzR. The most potent ligand of the ATBI series (10-methyl-3-phenyl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one 12) displayed a Ki value of 63 nM at the A1AR without binding appreciably to the adenosine A2A and A3 nor to the benzodiazepine receptor. Pharmacophore-based modeling studies in which 12 was compared against a set of well-established A1AR antagonists suggested that three hydrogen bonding sites (HB1 acceptor, HB2 and HB3 donors) and three lipophilic pockets (L1, L2, and L3) might be available to antagonists within the A1AR binding cleft. According to the proposed pharmacophore scheme, the lead compound 12 engages interactions with the HB2 site (via the N2 nitrogen) as well as with the L2 and L3 sites (through the pendant and the fused benzene rings). The results of these studies prompted the replacement of the methyl with more lipophilic groups at the 10-position (to fill the putative L1 lipophilic pocket) as a strategy to improve A1AR affinity. Among the new compounds synthesized and tested, the 3,10-diphenyl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one (23) was characterized by a Ki value of 18 nM which represents a 3.5-fold gain of A1AR affinity compared with the lead 12. A rhodopsin-based model of the bovine adenosine A1AR was built to highlight the binding mode of 23 and two well-known A1AR antagonists (III and VII) and to guide future lead optimization projects. In our docking simulations, 23 receives a hydrogen bond (via the N1 nitrogen) from the side chain of Asn247 (corresponding to the HB1 and HB2 sites) and fills the L1, L2, and L3 lipophilic pockets with the 10-phenyl, 3-phenyl, and fused benzene rings, respectively.
Asunto(s)
Bencimidazoles/síntesis química , Antagonistas de Receptores Purinérgicos P1 , Secuencia de Aminoácidos , Animales , Bencimidazoles/química , Bencimidazoles/metabolismo , Encéfalo/metabolismo , Bovinos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Ensayo de Unión Radioligante , Receptores Purinérgicos P1/metabolismoRESUMEN
Several derivatives, in which tryptamine, tyramine, and dopamine moieties are linked to the indole nucleus by an oxalyl bridge, were tested for their ability to displace the specific binding of [3H]flunitrazepam from bovine brain membranes. GABA ratio and in vivo tests for the most potent compounds showed they behave as inverse agonists at the benzodiazepine receptor (BzR). To better define the structure-activity relationship (SAR) of this kind of ligand, several phenylethylamine derivatives were synthesized to evaluate their affinity to BzR. Some of these derivatives (17, 21, 24, 26, and 30) were found to exhibit high affinity (Ki = 0.51-0.085 microM) for BzR and possessed a partial agonist activity, although their chemical structure is closely related to tryptamine 2-6, tyramine 7-11, and dopamine 12-16 derivatives. A different interaction of these ligands to the receptor site is hypothesized. Moreover, all the prepared 1-methyl derivatives exhibited very low binding affinity to BzR.
Asunto(s)
Dopamina/análogos & derivados , Indoles/metabolismo , Receptores de GABA-A/metabolismo , Triptaminas/química , Tiramina/análogos & derivados , Animales , Anticonvulsivantes , Unión Competitiva , Bovinos , Membrana Celular/metabolismo , Corteza Cerebral/metabolismo , Convulsivantes , Flunitrazepam/metabolismo , Indoles/síntesis química , Indoles/farmacología , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Acetic acid derivatives of [1,2,4]triazino[4,3-a]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-a]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC(50) = 0.36 microM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.
Asunto(s)
Acetatos/síntesis química , Aldehído Reductasa/antagonistas & inhibidores , Bencimidazoles/síntesis química , Inhibidores Enzimáticos/síntesis química , Triazinas/síntesis química , Acetatos/química , Acetatos/farmacología , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Sitios de Unión , Catarata/etiología , Catarata/prevención & control , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Galactosemias/complicaciones , Humanos , Modelos Moleculares , Soluciones Oftálmicas , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacologíaRESUMEN
A series of N-(arylalkyl)indol-3-ylglyoxylylamides (4-8) was synthesized as ligands of the benzodiazepine receptor (BzR) and tested for their ability to displace [(3)H]flumazenil from bovine brain membranes. The new compounds, bearing a branched (4) or a geometrically constrained benzyl/phenylethyl amide side chain (5-8), represent the continuation of our research on N-benzylindol-3-ylglyoxylylamides 1 (Da Settimo et al., 1996), N'-phenylindol-3-ylglyoxylohydrazides 2 (Da Settimo et al., 1998), and N-(indol-3-ylglyoxylyl)alanine derivatives 3 (Primofiore et al., 1989). A few indoles belonging to the previously investigated benzylamides 1 and phenylhydrazides 2 were synthesized and tested to enrich the SARs in these two series. The affinities and the GABA ratios of selected compounds for clonal mammalian alpha(1)beta(2)gamma(2), alpha(3)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzR subtypes were also determined. It was hypothesized that the reduced flexibility of indoles 4-8 would both facilitate the mapping of the BzR binding cleft and increase the chances of conferring selectivity for the considered receptor subtypes. In the series of indoles 4, the introduction of a methyl group on the benzylic carbon with the R configuration improved affinity of the 5-substituted (5-Cl and 5-NO(2)) derivatives, whereas it was detrimental for their 5-unsubtituted (5-H) counterparts. All S enantiomers were less potent than the R ones. Replacement of the methyl with hydrophilic substituents on the benzylic carbon lowered affinity. The isoindolinylamide side chain was tolerated if the 5-position was unsubstituted (K(i) of 5a = 123 nM), otherwise affinity was abolished (5b, c). All the 2-indanylamides 6 and (S)-1-indanylamides 8 were devoid of any appreciable affinity. The 5-Cl and 5-NO(2) (R)-1-indanylamides 7b (K(i) 80 nM) and 7c (K(i) 28 nM) were the most potent among the indoles 5-8 geometrically constrained about the side chain. The 5-H (R)-1-indanylamide 7a displayed a lower affinity (K(i) 675 nM). The SARs developed from the new compounds, together with those collected from our previous studies, confirmed the hypothesis of different binding modes for 5-substituted and 5-unsubstituted indoles, suggesting that the shape of the lipophilic pocket L(1) (notation in accordance with Cook's BzR topological model) is asymmetric and highlighted the stereoelectronic and conformational properties of the amide side chain required for high potency. Several of the new indoles showed selectivity for the alpha(1)beta(2)gamma(2) subtype compared with the alpha(3)beta(2)gamma(2) and alpha(5)beta(3)gamma(2) subtypes (e.g.: 4t and 7c bind to these three BzR isoforms with K(i) values of 14 nM, 283 nM, 239 nM, and 9 nM, 1960 nM, 95 nM, respectively). The GABA ratios close to unity exhibited by all the tested compounds on each BzR subtype were predictive of an efficacy profile typical of antagonists.
Asunto(s)
Glioxilatos/síntesis química , Indoles/síntesis química , Receptores de GABA-A/metabolismo , Amidas/síntesis química , Amidas/química , Amidas/metabolismo , Animales , Encéfalo/metabolismo , Bovinos , Glioxilatos/química , Glioxilatos/metabolismo , Técnicas In Vitro , Indoles/química , Indoles/metabolismo , Ligandos , Modelos Moleculares , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
A number of N-(indol-3-ylglyoxylyl)benzylamine derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. Some of these derivatives (9, 12, 14, 15, 17, 27, 34, 35, 38, 41, and 45) exhibited high affinity for the benzodiazepine receptor (BzR) with Ki values ranging from 67 to 11 nM. The GABA ratio and [35S]-tert-butylbicyclophosphorothionate binding data, determined for the most active compounds, showed that they elicit an efficacy profile at the BzR which depends on the kind of substituent present on the phenyl ring of the benzylamine moiety. Moreover, lengthening (propylamine derivatives 1-3) and shortening (aniline derivatives 46-54) of the distance between the phenyl ring and the amide group of the side chain gave compounds with a drastically lower binding potency. The biological results are discussed in the light of a recently proposed pharmacophore model and compared, by molecular modeling studies, with those obtained from effective BzR ligands.
Asunto(s)
Indoles/síntesis química , Receptores de GABA-A/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Indoles/química , Indoles/farmacología , Ratones , Modelos Moleculares , Ensayo de Unión Radioligante , Receptores de GABA-A/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended directly on the presence of the N(10)-H group and an aromatic ring at position 3. Some of them elicited a 2- or 3-fold higher affinity with respect to that of the indolylglyoxylylamide derivatives IV (R = H). The GABA ratio and [(35)S]-tert-butylcyclophosphorothionate binding data revealed an efficacy profile of partial inverse agonists/antagonists for compounds 1c,e,f,j,k, and of a partial agonist for 2c. This last compound proved to be effective in antagonizing pentylenetetrazole-induced seizures in mice. Attempts were made to interpret the structure-affinity relationships of compounds V in the light of possible tautomeric equilibria involving the ligands.
Asunto(s)
Bencimidazoles/síntesis química , Receptores de GABA-A/efectos de los fármacos , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Bencimidazoles/farmacología , Encéfalo/metabolismo , Bovinos , Convulsivantes/síntesis química , Convulsivantes/farmacología , Diazepam/antagonistas & inhibidores , Diazepam/farmacología , Flumazenil/farmacología , Moduladores del GABA/farmacología , Técnicas In Vitro , Ligandos , Membranas/efectos de los fármacos , Membranas/metabolismo , Ratones , Modelos Moleculares , Ensayo de Unión RadioliganteRESUMEN
A series of N'-phenylindol-3-ylglyoxylohydrazides, isosters of the N-benzylindol-3-ylglyoxylamide derivatives previously described by us, were synthesized and tested for their ability to displace [3H]Ro 15-1788 from bovine brain membranes. These compounds were designed with the aim of obtaining products which could exert an in vivo activity, thanks to a higher hydrosolubility and consequently a better bioavailability. Affinity was restricted to the derivatives unsubstituted in the 5 position of the indole nucleus (1, 6, 9, 12, 15, 18, 23, and 26), with Ki values ranging from 510 to 11 nM. The most active compounds (6, 9, 23, and 29) proved to be effective in antagonizing pentylenetetrazole-induced seizures. Molecular modeling studies were performed to rationalize the lack of affinity of hydrazides with a chloro or a nitro group in the 5 position of the indole nucleus. It was hypothesized that the conformational preference of the hydrazide side chain, characterized by a gauche disposition of lone pairs and substituents about the N-N bond, prevents all hydrazides from binding to the receptor similarly to other classes of indole analogues previously investigated. The potency of 5-H hydrazides was attributed to a binding mode which is not feasible for 5-Cl and 5-NO2 counterparts. This theoretical model of ligand-receptor interaction permitted a more stringent interpretation of structure-affinity relationships of hydrazides and of recently described benzylamide derivatives (Da Settimo et al. J. Med. Chem. 1996, 39, 5083-5091).
Asunto(s)
Encéfalo/metabolismo , Glioxilatos , Hidrazinas , Indoles , Modelos Moleculares , Receptores de GABA-A/efectos de los fármacos , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacología , Unión Competitiva , Bovinos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Convulsivantes/síntesis química , Convulsivantes/química , Convulsivantes/metabolismo , Convulsivantes/farmacología , Diazepam/farmacología , Flumazenil/metabolismo , Moduladores del GABA/metabolismo , Glioxilatos/síntesis química , Glioxilatos/química , Glioxilatos/metabolismo , Glioxilatos/farmacología , Hidrazinas/síntesis química , Hidrazinas/química , Hidrazinas/metabolismo , Hidrazinas/farmacología , Técnicas In Vitro , Indoles/síntesis química , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Ligandos , Ratones , Conformación Molecular , Receptores de GABA-A/metabolismo , Convulsiones/inducido químicamente , Relación Estructura-ActividadRESUMEN
Several 1-alkyl or 1-aralkyl substituted 2-aminobenzimidazole derivatives, bearing an acetic or acetohydroxamic group at 3-position, were synthesized. Some of these products were tested for their antiinflammatory and analgesic properties. These compounds exhibited an antiinflammatory activity lower than that of reference drug Indomethacin. Compound 2e showed the highest efficacy, but not in a dose-related manner. Only compounds 3a and 16 exhibited some analgesic activity, but at a very high dose.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Bencimidazoles/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/farmacología , Benzoquinonas , Carragenina , Edema/inducido químicamente , Edema/prevención & control , Masculino , Ratones , Dolor/inducido químicamente , Dolor/prevención & control , Ratas , Ratas Sprague-DawleyRESUMEN
The synthesis of some 2-aminobenzimidazole and indole amide derivatives containing a 2,6-dichloroaniline moiety is described. The preparation of a theophylline derivative is also reported. All the compounds tested showed no appreciable antihypertensive activity on spontaneously hypertensive rats.
Asunto(s)
Antihipertensivos/síntesis química , Bencimidazoles/síntesis química , Indoles/síntesis química , Animales , Bencimidazoles/farmacología , Presión Sanguínea/efectos de los fármacos , Clonidina/farmacología , Hipertensión/fisiopatología , Indoles/farmacología , Masculino , Ratas , Ratas Endogámicas SHRRESUMEN
The synthesis of a series of 2-aminobenzimidazole and indole amide derivatives containing the adamantyl moiety is described. The compounds, evaluated for in vitro anti-HIV and antitumor activities, were found to be moderately active or inactive, versus drug-treated controls, used for comparison purposes.
Asunto(s)
Adamantano/análogos & derivados , Antineoplásicos/química , Antivirales/química , Bencimidazoles/química , VIH/efectos de los fármacos , Adamantano/química , Adamantano/farmacología , Antineoplásicos/farmacología , Antivirales/farmacología , Bencimidazoles/farmacología , Línea Celular , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Células Tumorales CultivadasRESUMEN
Several N-(2-methyl or 1,2-dimethylindol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. The 2-methyl derivatives showed a lower affinity than the unmethylated analogues, and the 1,2-dimethyl derivatives practically lacked any affinity for the benzodiazepine receptor. The importance of the indole N-H group is therefore evidenced for an optimal interaction of these ligands with receptor site.
Asunto(s)
Aminoácidos/síntesis química , Indoles/síntesis química , Receptores de GABA-A/efectos de los fármacos , Aminoácidos/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Bovinos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Fenómenos Químicos , Química , Flunitrazepam/metabolismo , Glioxilatos/síntesis química , Glioxilatos/farmacología , Técnicas In Vitro , Indoles/farmacología , Espectroscopía de Resonancia Magnética , Membranas/efectos de los fármacos , Membranas/metabolismo , Receptores de GABA-A/metabolismo , Espectrofotometría InfrarrojaRESUMEN
Recently, several derivatives, in which tryptamine, tyramine, and dopamine moieties are linked to the indole nucleus by an oxalyl bridge, were tested for their affinity and efficacy at the benzodiazepine receptor (BzR). To better define the structure-activity relationships (SAR) several phenylethylamine derivatives were also synthesized and tested for their affinity at the BzR. Compounds bearing a protic group on the aromatic system of the side chain show a pharmacological profile of inverse agonist, while the products lacking this group behave as partial agonist. We now report the affinity data at the BzR of new compounds in which the distance between the phenyl ring and the amide group of the side chain has been changed. The benzylamine derivatives showed a good affinity at the BzR, generally higher than that of the phenylethylamine derivatives. In this series the pharmacological profile showed to be opposite to that of the corresponding phenylethylamine derivatives, since the compounds substituted with protic groups on the phenyl ring behaved as partial agonists. Moreover, a probable interaction with the receptor site is hypothesized.
Asunto(s)
Indoles/síntesis química , Receptores de GABA-A/efectos de los fármacos , Animales , Bovinos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Técnicas In Vitro , Indoles/metabolismo , Indoles/farmacología , Receptores de GABA-A/metabolismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/metabolismoRESUMEN
A series of 1-alkyl substituted 2-methylaminobenzimidazole derivatives was prepared and tested. Some of them were assayed orally in the rat for antiinflammatory and analgesic properties. The compounds did not exhibit any significant activity compared with reference drug levels.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Bencimidazoles/síntesis química , Animales , Antiinflamatorios , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Bencimidazoles/química , Bencimidazoles/uso terapéutico , Femenino , Masculino , Ratones , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Estándares de Referencia , Relación Estructura-ActividadRESUMEN
Derivatives of 4-substituted 1,2-benzisothiazole-1,1-dioxide alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested in rat lens enzyme. The acetic derivatives 10, 12, and 16a-d proved to be much more potent inhibitors than the propionic derivatives 11, 13, and 17a-d. The presence of an acyl moiety on the amino group in position 4 of the acetic derivatives 16a-d led to a significant increase in activity with respect to the parent compound 14. One of the most active compounds in vitro, 10, was also evaluated in vivo as an inhibitor of glutathione lens depletion in galactosemic rats, but it did not show any activity in maintaining the rat lens glutathione level, probably due to problems of ocular bioavailability or metabolism.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Cristalino/enzimología , Tiazoles/síntesis química , Animales , Fenómenos Químicos , Química Física , Inhibidores Enzimáticos/farmacología , Galactosemias/enzimología , Galactosemias/metabolismo , Glutatión/metabolismo , Técnicas In Vitro , Cristalino/metabolismo , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacologíaRESUMEN
The synthesis and preliminary pharmacological evaluation of 2-aminobenzimidazole amide derivatives are reported. None of these compounds showed antilipidemic or platelet antiaggregatory activity comparable to that of drugs used in therapy.
Asunto(s)
Bencimidazoles/síntesis química , Hipolipemiantes/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Animales , Bencimidazoles/farmacología , Fenómenos Químicos , Química , Hiperlipidemias/inducido químicamente , Hiperlipidemias/tratamiento farmacológico , Técnicas In Vitro , Masculino , Agregación Plaquetaria/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
The synthesis of benzimidazoquinazoline derivatives bearing different alkylamino side chains is reported. All new compounds tested by means of an in vitro assay exhibit antiproliferative activity toward human tumor cell lines. The cytotoxic effect depends on the type of side chain inserted in the planar nucleus and in some cases it is comparable to that of the well-known drug ellipticine. In order to understand the mechanism of action of these compounds, the interaction with DNA has been investigated. Linear flow dichroism measurements allowed us to verify the formation of a molecular complex with DNA and the corresponding geometry of interaction. Intrinsic binding constants have also been evaluated by performing fluorimetric titrations.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , ADN de Neoplasias/efectos de los fármacos , Quinazolinas/síntesis química , Quinazolinas/farmacología , Dicroismo Circular , ADN/química , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , Células Tumorales CultivadasRESUMEN
A number of benzyl and phenylethyl esters of indol-3-ylglyoxylic acid were synthesized and tested for their ability to displace [3H]Ro 15-1788 binding from bovine brain membranes. In these new compounds the oxygen atom of the ester function replaced the amide NH group of a class of previously described indolylglyoxylylamides, since it is reported in literature that in the beta-carboline series an ester function is more favourable to the activity than an amide group. However, none of the compounds showed an affinity at the Benzodiazepine receptor higher than that of the corresponding amides, demonstrating that the presence of the amide NH group is favourable to the interaction of ligands with the receptor site.
Asunto(s)
Amidas/química , Ésteres/química , Glioxilatos/química , Indoles/química , Receptores de GABA-A/metabolismo , Amidas/metabolismo , Animales , Encéfalo/metabolismo , Bovinos , Membrana Celular/metabolismo , Ésteres/metabolismo , Antagonistas de Receptores de GABA-A , Glioxilatos/metabolismo , Técnicas In Vitro , Indoles/metabolismo , Estructura MolecularRESUMEN
A number of furoylindoles were synthesized with the aim of obtaining structurally more restrained analogues of the previously described indoleglyoxylylamides, which are high affinity ligands at the benzodiazepine receptor. In these new compounds, the oxygen atom of the oxalyl CO(2) is inserted into the rigid furan ring. However, unlike the glyoxylylamides, they proved to be incapable of interacting with the benzodiazepine receptor. To rationalize these results, molecular electrostatic potentials were calculated; these indicated a positive electrostatic potential region for the furan oxygen, which thus prevents the formation of a hydrogen bond necessary for interaction with the receptor. Nevertheless, these findings confirmed that the CO(2) of the indoleglyoxylylamide derivatives represents one of the principal points of interaction with the receptor site for these kinds of ligands, as previously hypothesized by us.