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PubMed1997

Divergent modes of action among cationic allosteric modulators of muscarinic M2 receptors.

We tested the hypothesis that structurally related modulators of ligand binding to muscarinic M2 receptors may not use a common recognition site. The applied test compounds are potent allosteric modulators [i.e., two bispyridinium model compounds substituted symmetrically either with phthalimidomethyl (WDuo3) or dichlorobenzyl (Duo3), a phthalimidoethyl-substituted hexamethonium compound (W84), alcuronium, and, for sake of comparison, gallamine]. As introduced by Ellis and Seidenberg as a tool to check for a common allosteric site [Mol. Pharmacol. 42:638-641 (1992)], obidoxime was used to antagonize the actions of the test compounds. The allosteric delay of the dissociation of [3H]N-methylscopolamine ([3H]NMS) from porcine heart muscarinic receptors was measured in 5 mM sodium/potassium phosphate buffer (4 mM Na2HPO4 and 1 mM KH2PO4, pH 7.4) at 23 degrees (control t1/2 = 4 min). The concentration-effect curve of obidoxime, which has a weak potency and submaximal efficacy to allosterically retard [3H]NMS dissociation, was better described with a two-site model than with a one-site model. The concentration-effect curves of the test compounds for the allosteric delay of [3H]NMS dissociation were shifted to the right in the presence of obidoxime, yet to a different extent. For WDuo3, W84, alcuronium, and gallamine, the shift induced by increasing concentrations of obidoxime was compatible with a competitive interplay. The pKb values of obidoxime against these modulators lay in a narrow range from pKb = 4.70 with gallamine to pKb = 4.16 with WDuo3. In contrast, the ability of obidoxime to shift the concentration-effect curve of Duo3 was weak (pA2 = 3.00) and not compatible with a competitive interplay. In conclusion, cationic allosteric modulators may stabilize [3H]NMS binding to M2 receptors by divergent modes of allosteric action. The findings suggest that the M2 receptor protein contains more than one allosteric recognition site on its extracellular face.

Animals↗

PubMed1988

A novel GABAA antagonist [3H]SR 95531: microscopic analysis of binding in the rat brain and allosteric modulation by several benzodiazepine and barbiturate receptor ligands.

Recent reports have demonstrated that the synthetic gamma-aminobutyric acid (GABA)-derivative, SR 95531 [2-(3'-carbethoxy-2'-propyl)-3-amino-6-paramethoxy-phenyl-pyrid azinium bromide], possesses selective GABAA antagonistic properties. Because of its potency for recognition of GABAA sites, this agent has been used to identify GABAA receptors. In the present investigation, we studied the binding of [3H]SR 95531 to tissue sections of rat brain using microscopic analysis of receptor localization. The appropriate binding conditions for defining GABAA receptors with this radioligand were obtained by determining the dissociation and association kinetics, and performing saturation and displacement studies. Using membrane preparations from whole rat brain (or brain regions representing cortex, striatum, hippocampus, midbrain-thalamus, medulla-pons and cerebellum), saturation and displacement studies were analyzed, and allosteric modulation of [3H]SR 95531 binding was examined by including several benzodiazepine and barbiturate receptor ligands in the incubation media. To assess the stereoselective properties of [3H]SR 95531 binding in rat membranes, numerous barbiturates were added during the incubation. The binding of [3H]SR 95531 was demonstrated to be saturable, specific and to bind with relatively high affinity to low-affinity GABAA sites. Scatchard analysis performed on saturation data of binding to tissue sections showed a dissociation constant (KD) of 42.4 nM and a maximum number of binding sites (Bmax) of 105.8 fmol/mg tissue. Microscopic analysis showed that intermediate to high densities of [3H]SR 95531 binding occurred in brain regions containing intermediate to high densities of low-affinity GABAA receptor sites. The binding of [3H]SR 95531 to membranes also appeared to occur at low-affinity GABAA sites. Results from competition studies demonstrated that [3H]SR 95531 is displaceable by GABAA agents and displaced preferentially by GABAA antagonists. Scatchard analysis of saturation experiments from membrane preparations indicated that the KD and Bmax from the centrifugation assay was 53.0 nM and 4.26 pmol/mg protein, respectively. Using the filtration assay, binding to membranes yielded a KD value of 45.6 nM and a Bmax of 0.77 pmol/mg protein. The allosteric modulation data demonstrated that numerous benzodiazepine and barbiturate agents inhibited [3H]SR 95531 binding and this varied according to brain region. Several barbiturates included in the incubation media exhibited a stereoselective inhibition of [3H]SR 95531 binding to whole rat brain membranes.(ABSTRACT TRUNCATED AT 400 WORDS)

Allosteric Regulation↗

PubMed2002

LY404187: a novel positive allosteric modulator of AMPA receptors.

LY404187 is a selective, potent and centrally active positive allosteric modulator of AMPA receptors. LY404187 preferentially acts at recombinant human homomeric GluR2 and GluR4 versus GluR1 and GluR3 AMPA receptors. In addition, LY404187 potentiates the flip splice variant of these AMPA receptors to a greater degree than the flop splice variant. In both recombinant and native AMPA receptors, potentiation by LY404187 displays a unique time-dependent growth that appears to involve a suppression of the desensitization process of these ion channels. LY404187 has been shown to enhance glutamatergic synaptic transmission both in vitro and in vivo. This augmentation of synaptic activity is due to the direct potentiation of AMPA receptor function, as well as an indirect recruitment of voltage-dependent NMDA receptor activity. Enhanced calcium influx through NMDA receptors is known to be a critical step in initiating long-term modifications in synaptic function (e.g., long-term potentiation, LTP). These modifications in synaptic function may be substrates for certain forms of memory encoding. Consistent with a recruitment of NMDA receptor activity, LY404187 has been shown to enhance performance in animal models of cognitive function requiring different mnemonic processes. These data suggest that AMPA receptor potentiators may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as schizophrenia. In addition, LY404187 has been demonstrated to be efficacious in animal models of behavioral despair that possess considerable predictive validity for antidepressant activity. Although the therapeutic efficacy of AMPA receptor potentiators in these and other diseases will ultimately be determined in the clinic, evidence suggests that the benefit of these compounds will be mediated by multiple mechanisms of action. These mechanisms include direct enhancement of AMPA receptor function, secondary mobilization of intracellular signaling cascades, and prolonged modulation of gene expression.

Action Potentials↗

PubMed1994

Interaction of ethanol and allosteric modulators with GABAA-activated currents in adult medial septum/diagonal band neurons.

Behavioral and electrophysiological studies suggest that neurons in the medial septum may express ethanol sensitive GABAA receptors. In the present study, patch-clamp recordings of whole-cell currents were used to directly characterize the ethanol sensitivity of GABAA receptors on acutely dissociated neurons, isolated from the medial septum/nucleus of the diagonal band (MS/nDB) of the adult rat brains. MS/nDB neurons displayed inward currents in response to GABA applied rapidly with a large-bore dual pipette system. The currents were mediated by the activation of GABAA receptors, since they reversed near the calculated reversal potential for chloride and were completely blocked by bicuculline. GABA responses were concentration dependent with an EC50 of 8.7 microM GABA and a slope of 1.35 suggesting cooperativity. Pharmacologically relevant concentrations of ethanol (3-300 mM) neither significantly increased nor decreased mean responses to GABA in neurons from Sprague Dawley or High Alcohol Sensitivity (HAS) rats. Mean GABA currents were significantly increased by 300 mM ethanol in neurons from 'ethanol sensitive' Fischer 344, ACI and Wistar Kyoto inbred rats. In subsets of neurons, 12.5 to 57.1% of those tested from these 5 rats strains, ethanol (30-300 mM) significantly increased GABA currents by > or = 20%. An additional, 10 percent of cells from Sprague Dawley rats showed ethanol-induced inhibition of GABA-activated current by < or = 20%. Allosteric modulators pentobarbital (10 microM), midazolam (1 microM) and lanthanum (300 microM), enhanced, while zinc (30 microM) decreased GABA-activated currents in all neurons, consistent with the well-known actions of these agents. These results suggest that GABAA receptors on MS/dDB neurons are pharmacologically similar to those on other neurons with respect to regulation by allosteric modulators. On the other hand, ethanol sensitivity of GABAA receptors varies considerably from cell to cell ranging from significant enhancement to inhibition of GABA-activated current.

Allosteric Regulation↗

PubMed2004

Allosteric modulation of semicarbazide-sensitive amine oxidase activities in vitro by imidazoline receptor ligands.

1. Evidence indicates that imidazoline I(2) binding sites (I(2)BSs) are present on monoamine oxidase (MAO) and on soluble (plasma) semicarbazide-sensitive amine oxidase enzymes. The binding site on MAO has been described as a modulatory site, although no effects on activity are thought to have been observed as a result of ligands binding to these sites. 2. We examined the effects in vitro of several imidazoline binding site ligands on activities of bovine plasma amine oxidase (BPAO) and porcine kidney diamine oxidase (PKDAO) in a spectrophotometric protocol. 3. While both enzymes were inhibited at high concentrations of all ligands, clonidine, cirazoline and oxymetazoline were seen, at lower concentrations, to increase activity of BPAO versus benzylamine, but not of PKDAO versus putrescine. This effect was substrate dependent, with mixed or biphasic inhibition of spermidine, methylamine, p-tyramine and beta-phenylethylamine oxidation observed at cirazoline concentrations that increased benzylamine oxidation. 4. With benzylamine as substrate, clonidine decreased K(M) (EC(50) 8.82 microm, E(max) 75.1% of control) and increased V(max) (EC(50) 164.6 microm, E(max) 154.1% of control). Cirazoline decreased V(max) (EC(50) 2.15 microm, E(max) 91.4% of control), then decreased K(M) (EC(50) 5.63 microm, E(max) 42.6% of control) and increased V(max) (EC(50) 49.0 microm, E(max) 114.4% of decreased V(max) value). 5. Data for clonidine fitted a mathematical model for two-site nonessential activation plus linear intersecting noncompetitive inhibition. Data for cirazoline were consistent with involvement of a fourth site. 6. These results reveal an ability of imidazoline ligands to modulate BPAO kinetics allosterically. The derived mechanism may have functional significance with respect to modulation of MAO by I(2)BS ligands.

Allosteric Regulation↗

PubMed2000

Agonist binding and function at the human alpha(2A)-adrenoceptor: allosteric modulation by amilorides.

It has been found previously that amilorides act via an allosteric site on the alpha(2A)-adrenergic receptor to strongly inhibit antagonist binding. In this study, allosteric modulation of agonist binding and function at the alpha(2A)-adrenergic receptor was explored. The dissociation rate of the agonist [(3)H]UK14304 from alpha(2A)-receptors was decreased by the amilorides in a concentration-dependent manner. This contrasts with the increases in (3)H-antagonist dissociation rate found previously. The agonist-amiloride analog interaction data could be fitted to equations derived from the ternary complex allosteric model. The calculated log affinities of the amilorides at the [(3)H]UK14304-occupied receptor increased with the size of the 5-N-alkyl side chain and ranged from 2.4 for amiloride to 4.2 for 5-(N,N-hexamethylene)-amiloride. The calculated negative cooperativities cover a narrow range, in sharp contrast to the broad range found for antagonist-amiloride analog interactions. The effects of the amilorides on the agonist actions of UK14304, epinephrine, and norepinephrine were explored using a [(35)S]GTPgammaS functional assay, and the parameters calculated for the cooperativities and affinities of the UK14304-amiloride analog interactions, using the equation derived from the ternary complex allosteric model, were in good agreement with those derived from the kinetic studies. Therefore both the binding and functional data provide further support for the existence of a well defined allosteric site on the human alpha(2A)-adrenergic receptor. The binding mode of the amilorides at the agonist-occupied and antagonist-occupied receptor differs markedly but, within each group, the structure of either the agonist or the antagonist examined has only a slight effect on the allosteric interactions.

Adrenergic alpha-Agonists↗

PubMed1997

Molecular rigidity and potency of bispyridinium type allosteric modulators at muscarinic M2-receptors.

Several bispyridinium compounds have been shown to be potent allosteric modulators of ligand binding to muscarinic M2-receptors. ,,Uno compounds" are benzyl derivatives of the bispyridinium "TMB4" (trimethylene-bis-[4-hydroxy-iminomethyl-pyridinium]). To gain more insight into structure activity relationships, eleven derivatives with varying structure of the oxime-linked aromatic substituent were tested for their ability to inhibit the equilibrium-binding of [3H]N-methylscopolamine ([3H]NMS) in guinea pig cardiac membranes and to retard [3H]NMS-dissociation allosterically. At a concentration of 3 microM, all compounds reduced [3H]NMS-binding to about 40 % of the control level, indicating a similar potency to inhibit the association of [3H]NMS. Allosteric retardation of [3H]NMS-dissociation required higher concentrations. Comparing the effects of the compounds at 30 and 300 microM, respectively, revealed considerable differences in potency. Therefore, the concentration-dependency of the delay of [3H]NMS-dissociation was determined for selected compounds. The results indicate that introduction of a benzyl-moiety into TMB4 leads to a 20-fold increase in allosteric potency. A further increment by a factor of 10 is obtained with the 2,6-dichlorobenzyl-substitution and with the naphthyl-derivative. The other compounds were less potent. An inverse correlation was found between the rotational freedom of the aromatic substituent and the allosteric potency. In conclusion, the aromatic moiety of non-symmetric bispyridinium-type modulators does not seem to be part of the pharmacophore involved in the inhibitory effect on the association of [3H]NMS. In contrast, a rigid aromatic lateral moiety appears to be essential for the interaction with the recognition site mediating the allosteric delay of [3H]NMS dissociation from muscarinic M2-receptors.

Allosteric Regulation↗

PubMed2004

Effects of the allosteric modulator SCH-202676 on adenosine and P2Y receptors.

The G protein-coupled receptor allosteric modulator SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5-(2H)-ylidene)methanamine), which affects a wide range of structurally unrelated G protein-coupled receptors, has highly divergent effects on purine receptors. SCH-202676 inhibited radioligand binding to human adenosine A(1), A(2A), and A(3) receptors (IC(50) = 0.5-0.8 microM) and affected dissociation kinetics, but at the human P2Y(1) nucleotide receptor it had no effect. SCH-202676 (10 microM) selectively accelerated agonist dissociation at adenosine A(3) receptors and either slowed (adenosine A(1) receptors) or accelerated (adenosine A(2A) receptors) antagonist dissociation. Thus, SCH-202676 differentially modulated A(1), A(2A), and A(3) receptors as well as agonist- and antagonist-occupied receptors.

Allosteric Regulation↗

PubMed1992

DNA allosterically modulates the steroid binding domain of the estrogen receptor.

The ability of DNA to allosterically alter the conformation of the estrogen receptor's (ER) steroid binding domain was investigated. Using dissociation kinetics we observed that when DNA was bound to the DNA binding domain of the rat uterine ER the rate of estrogen dissociation from the steroid binding domain increased almost 2-fold. This change in the rate of estrogen dissociation depended on the concentration of DNA used and correlated with the thermodynamic binding affinities (Kd) of the ER for two different DNA sequences. We were unable to detect a DNA-induced change in the trypsin cleavage pattern of the amino terminal end of the ER. Using a whole cell dissociation kinetic assay with MCF-7 breast cancer cells we observed a 7-fold slower rate of estrogen dissociation from the ER within the cell than from the ER in vitro. This suggests that additional factors, other than DNA binding, may modify the steroid binding domain within the cell. We conclude that DNA can allosterically modulate the structure of the steroid binding domain of the ER, and we hypothesize that this conformational change may be necessary for the full transcriptional activity of the ER.

Allosteric Regulation↗

PubMed2005

Allosteric modulators affect the internalization of human adenosine A1 receptors.

To study the effect of allosteric modulators on the internalization of human adenosine A(1) receptors, the receptor was equipped with a C-terminal yellow fluorescent protein tag. The introduction of this tag did not affect the radioligand binding properties of the receptor. CHO cells stably expressing this receptor were subjected during 16 h to varying concentrations of the agonist N(6)-cyclopentyladenosine (CPA) in the absence or presence of 10 microM of the allosteric enhancer PD 81,723 ((2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone) or the allosteric inhibitor SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5(2H)-ylidene)methanamine). CPA itself was able to internalize 25% and 40% of the receptors at a concentration of 400 nM or 4 muM, respectively. Addition of either PD 81,723 or SCH-202676 alone had no effect on internalization. However, with PD 81,723 a slight amount of internalization was obtained already at 40 nM of CPA and at 400 nM CPA 59% of the receptors internalized. SCH-202676 on the other hand effectively prevented CPA-induced internalization of the receptor.

Adenosine↗

PubMed2006

Pharmacological and computational analysis of alpha-subunit preferential GABA(A) positive allosteric modulators on the rat septo-hippocampal activity.

Clinically most active anxiolytic drugs are positive allosteric modulators (PAMs) of GABA(A) receptors, represented by benzodiazepine compounds. Due to their non-selective profile, however, they potently modulate several sup-type specific GABA(A) receptors, contributing to their broad-range side effects. Based on observations in genetically altered mice, however, it has been proposed that anxiolytic action of benzodiazepines is predominantly mediated by GABA(A) alpha2/3 subunit-containing receptors. In the present study we analyzed the actions of the preferential GABA(A) alpha1 and alpha2/3 PAMs, zolpidem and L-838417, respectively on hippocampal EEG and medial septum neuronal activity in anesthetized rats. In parallel, a computational model was constructed to model pharmacological actions of these compounds on the septo-hippocampal circuitry. The present results demonstrated that zolpidem inhibited theta oscillation both in the hippocampus and septum, and profoundly inhibited firing activity of septal neurons. L-838417 also inhibited hippocampal and septal theta oscillation, however, it did not significantly alter firing rate activity of septal neurons. Our computational model showed that cessation of periodic firing of hippocampo-septal neurons, representing absence of hippocampal theta activity, disrupted oscillation of septal units, without altering their overall firing activity, similar to changes observed in our in vivo experiments following administration of L-838417. Understanding the correlation between changes in septo-hippocampal activity and actions of selective modulators of GABA(A) subtype receptor modulators would further advance design of anxiolytic drugs.

Action Potentials↗

PubMedDate not supplied

Positive effects of allosteric modulators on the binding properties and the function of muscarinic acetylcholine receptors.

Data are reviewed indicating that allosteric modulators can enhance the affinities of muscarinic receptors for their antagonists and agonists, that the enhancement of the affinity for agonists is relevant functionally, and that the allosterically induced conformational change also affects the interaction between the receptors and the G proteins.

Allosteric Regulation↗

PubMed1999

Mutation at the putative GABA(A) ion-channel gate reveals changes in allosteric modulation.

We have mutated a conserved leucine in the putative membrane-spanning domain to serine in human GABA(A) beta2 and investigated the actions of a number of GABA(A) agonists, antagonists and modulators on human alpha1beta2deltaL259Sgamma2s compared to wild type alpha1beta2gamma2s GABA(A) receptors, expressed in Xenopus oocytes. The mutation resulted in smaller maximum currents to gamma-aminobutyric acid (GABA) compared to alpha1beta2gamma2s receptors, and large leak currents resulting from spontaneous channel opening. As reported, this mutation significantly decreased the GABA EC50 (110 fold), and reduced desensitization. Muscimol and the partial agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and piperidine-4-sulphonic acid (P4S) also displayed a decrease in EC50. In addition to competitively shifting GABA concentration response curves, the antagonists bicuculline and SR95531 both inhibited the spontaneous channel activity on alpha1beta2deltaL259Sgamma2s receptors, with different degrees of maximum inhibition. The effects of a range of allosteric modulators, including benzodiazepines and anaesthetics were examined on a submaximal GABA concentration (EC20). Compared to wild type, none of these modulators potentiated the EC20 response of alpha1beta2deltaL259Sgamma2s receptors, however they all directly activated the receptor in the absence of GABA. To conclude, the above mutation resulted in receptors which exhibit a degree of spontaneous activity, and are more sensitive to agonists. Benzodiazepines and other agents modulate constitutive activity, but positive modulation of GABA is lost. The competitive antagonists bicuculline and SR95531 can also act as allosteric channel modulators through the same GABA binding site.

Allosteric Regulation↗

PubMed2003

Allosteric modulation of human P-glycoprotein. Inhibition of transport by preventing substrate translocation and dissociation.

The human multidrug transporter P-glycoprotein (Pgp, ABCB1) contributes to the poor bioavailability of many anticancer and antimicrobial agents as well as to drug resistance at the cellular level. For rational design of effective Pgp inhibitors, a clear understanding of its mechanism of action and functional regulation is essential. In this study, we demonstrate that inhibition of Pgp-mediated drug transport by cis-(Z)-flupentixol, a thioxanthene derivative, occurs through an allosteric mechanism. Unlike competitive inhibitors, such as cyclosporin A and verapamil, cis-(Z)-flupentixol does not interfere with substrate ([(125)I]iodoarylazidoprazosin) recognition by Pgp, instead it prevents substrate translocation and dissociation, resulting in a stable but reversible Pgp-substrate complex. cis-(Z)-Flupentixol-induced complex formation requires involvement of the Pgp substrate site, because agents that either physically compete (cyclosporin A) for or indirectly occlude (vanadate) the substrate-binding site prevent formation of the complex. Allosteric modulation by cis-(Z)-flupentixol involves a conformational change in Pgp detectable by monoclonal antibody UIC2 binding to a conformation-sensitive external epitope of Pgp. The conformational change observed is distinct from that induced by Pgp substrates or competitive inhibitors. A single amino acid substitution (F983A) in TM12 of Pgp that impairs inhibition by cis-(Z)-flupentixol of Pgp-mediated drug transport also affects stabilization of the Pgp-substrate complex as well as the characteristic conformational change. Taken together, our results describe the molecular mechanism by which the Pgp modulator cis-(Z)-flupentixol allosterically inhibits drug transport.

3T3 Cells↗

PubMed2003

Cholinergic nicotinic receptors: competitive ligands, allosteric modulators, and their potential applications.

Discovery of the important role played by nicotinic acetylcholine receptors (nAChRs) in several CNS disorders has called attention to these membrane proteins and to ligands able to modulate their functions. The existence of different subtypes at multiple levels has complicated the understanding of this receptor's physiological role, but at the same time has increased the efforts to discover selective compounds in order to improve the pharmacological characterization of this kind of receptor and to make the possible therapeutical use of its modulators safer. This review focuses on the structure of new ligands for nAChRs, agonists, antagonists and allosteric modulators, and on their possible applications.

Allosteric Regulation↗

PubMed2002

Allosteric modulation of muscarinic receptor signaling: alcuronium-induced conversion of pilocarpine from an agonist into an antagonist.

Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent alcuronium is known to bind with similar affinity to the M(2) subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M(2)-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC(50, Alc) = 5.63) without any effect on the EC(50) of pilocarpine, consistent with an allosteric mechanism. In contrast, alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (pK(A, Alc) = 5.54). If pilocarpine remained receptor bound in the presence of alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 microM alcuronium. Measuring guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in CHO-M(2) membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [(35)S]GTPgammaS binding (pIC(50, Alc) = 5.47) without shift in EC(50), whereas it competitively shifted the response to oxotremorine M (pK(A, Alc) = 5.97). [(3)H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, alcuronium converted the agonist pilocarpine into an antagonist-a novel type of functional allosteric interaction.

Alcuronium↗

PubMed2004

In vivo effectiveness of CGP7930, a positive allosteric modulator of the GABAB receptor.

The present study was aimed at assessing the in vivo effectiveness of the positive allosteric modulator of the gamma-aminobutyric acidB (GABAB) receptor, CGP7930 [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol]. The synergistic potentiation of GABAB receptor functioning, previously observed in different in vitro assays, has been confirmed in the present work, where pretreatment with CGP7930 (10-170 mg/kg, i.p.) resulted in a marked potentiation of the sedative/hypnotic effect of the GABAB receptor agonists, baclofen (40 mg/kg, i.p.) and gamma-hydroxybutyric acid (500 mg/kg, i.p.), in DBA mice. Pretreatment with the GABAB receptor antagonist, SCH 50911 [(S)-5,5-dimethyl-2-morpholine acetic acid; 100 mg/kg, i.p.], resulted in a complete blockade of the sedative/hypnotic effect of the combination of CGP7930 with either baclofen or gamma-hydroxybutyric acid. These results confirm that CGP7930 may constitute an interesting tool for pharmacological studies in the GABAB receptor field.

Animals↗

PubMed1996

Comparison of structurally different allosteric modulators of muscarinic receptors by self-organizing neural networks.

Similarities in the molecular structure and surface properties of the allosteric modulators of muscarinic receptors, alcuronium, gallamine, tubocurarine, and the hexamethonium compound W84, a well-known pharmacological tool, are explored. The analysis of the molecular electrostatic potential (MEP) as well as of the shape of the molecular surface is performed by self-organizing neural networks. A distorted sandwich conformation of W84 is suggested to be the active form. The importance of the MEP for binding of these compounds could be established.

Alcuronium↗