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PubMed2002

Nicotinic cholinergic modulation: galantamine as a prototype.

Nicotinic acetylcholine receptor pharmacology is becoming increasingly important in the clinical symptomatology of neurodegenerative diseases in general and of cognitive and behavioral aspects in particular. In addition, the concept of allosteric modulation of nicotinic acetylcholine receptors has become a research focus for the development of therapeutic agents. In this review the scientific evidence for changes in nicotinic acetylcholine receptors in Alzheimer's disease is described. Within this context, the pharmacology of galantamine, a recently approved drug for cognition enhancement in Alzheimer's disease, is reviewed along with preclinical studies of its efficacy on learning and memory. Galantamine modestly inhibits acetylcholinesterase and has an allosteric potentiating ligand effect at nicotinic receptors. The data collected in this review suggest that the unique combination of acetylcholinesterase inhibition and nicotinic acetylcholine receptor modulation offers potentially significant benefits over acetylcholinesterase inhibition alone in facilitating acetylcholine neurotransmission.

Acetylcholine↗
PubMed2003

Allosteric adenosine receptor modulation reduces hypersensitivity following peripheral inflammation by a central mechanism.

Activation of adenosine A1 receptors by endogenous adenosine or synthetic agonists produces antinociception in animal models of acute pain and also reduces hypersensitivity in models of inflammatory and nerve-injury pain. Allosteric adenosine modulators facilitate and potentiate the action of adenosine agonists at the A1 receptors. The purpose of the current study was to examine the effect and site of action for an allosteric adenosine modulator, T62 [2-amino-3-(4-chlorobenzoyl)-5,6, 7,8-tetrahydrobenzothiophene], in rat models of acute pain and inflammation. Intrathecal (i.t.) T62 did not change the withdrawal latency or threshold of normal rats to acute heat or to acute paw pressure. In contrast, i.t. T62 reversed thermal hypersensitivity in carrageenin-inflamed rats. Subcutaneous (s.c.) injection of T62 into the inflamed paw had no such effect. To investigate a potential site of action on nociceptors, single-unit afferent activity to mechanical stimuli on A delta- and C-fibers was examined in normal or carrageenin-inflamed rats before and after intravenous (i.v.) T62 administration. Intravenous T62, 3 mg/kg, had no significant effect in either normal or inflamed conditions. These results support previous studies to suggest that adenosine receptor modulators lack efficacy to acute nociceptive stimuli in the normal condition, but reduce hypersensitivity during inflammation through a central mechanism.

Afferent Pathways↗
PubMed2002

Anesthetic and ethanol effects on spontaneously opening glycine receptor channels.

Strychnine-sensitive glycine receptors mediate inhibitory neurotransmission occurring in the brain stem and spinal cord. Alcohols, volatile anesthetics and inhaled drugs of abuse are positive allosteric modulators of glycine receptor function, normally enhancing function only in the presence of glycine. A complication in studying allosteric actions on ligand-gated ion channels is in the dissection of their effects on neurotransmitter binding from their effects on channel opening. Mutation of an aspartate residue at position 97 to arginine in the glycine receptor alpha1 subunit simulated the effects of glycine binding, producing receptors that exhibited tonic channel opening in the absence of neurotransmitter; i.e. these receptors demonstrated a dissociation of channel opening from neurotransmitter binding. In these receptors, ethanol, enflurane, chloroform, halothane, 1,1,1-trichloroethane and toluene elicited inward currents in the absence of glycine. We previously identified mutations on ligand-gated ion channels that eliminate ethanol, anesthetic and inhalant actions (such as S267I on alpha1 glycine receptors). The double mutant (D97R and S267I) receptors were both constitutively active and resistant to the enhancing effects of ethanol and enflurane. These data demonstrate that ethanol and volatile anesthetics can affect glycine receptor channel opening independently of their effects on enhancing neurotransmitter binding.

Allosteric Regulation↗
PubMed2003

Neurosteroid modulation of the presynaptic NMDA receptors regulating hippocampal noradrenaline release in normal rats and those exposed prenatally to diazepam.

Prenatal exposure to diazepam (DZ), a positive allosteric modulator of the gamma-aminobutyric acid(A) (GABA(A)) receptor complex, exerts profound effects that become more evident during puberty and in many cases are sex-specific, suggesting that such exposure interferes with the activity of steroid hormones. Apart from their well known effects on the genome, the reduced metabolites of many steroid hormones also interact directly with membrane receptors, including those for N-methyl-D-aspartate (NMDA). In this study, we compared the effects of several neurosteroids on NMDA receptors from normal rats and those exposed in utero to DZ (1.25mg/kg per day) from the 14th through the 20th day of gestation. In superfused rat hippocampal synaptosomes, activation of the NMDA receptor stimulates the basal release of [3H]noradrenaline ([3H]NA), which was used in our study as an index of receptor function. [3H]NA release was evoked in a concentration-dependent manner by NMDA (100 microM) plus glycine (GLY). The maximal increase (68.23+/-3.86%) with respect to basal release was achieved with a GLY concentration of 10 microM, and the EC(50) for GLY was 0.1 microM. Release stimulated by 100 microM NMDA + 0.1 microM GLY was not modified by any of the neurosteroids tested, with the exception of pregnenolone sulfate (PREG-S), which produced a 78.57+/-3.94% reduction in release at the maximal concentration used (0.3 microM). In synaptosomes from animals exposed in utero to DZ, the inhibitory effect of PREG-S was reduced by 46.55+/-2.33%. Given the important roles played by NMDA receptors in physiological and pathological processes within the central nervous system (CNS), characterization of NMDA receptor modulation is an important objective. The fact that this modulation can be altered by exposure in utero to DZ indicates that the behavioral abnormalities observed in exposed animals might be partially attributed to an altered sensitivity of NMDA receptors to the modulatory effects of neurosteroids.

Animals↗
PubMed2000

Neurosteroid modulation of GABA IPSCs is phosphorylation dependent.

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) facilitates GABA(A) receptor-mediated ionic currents via allosteric modulation of the GABA(A) receptor. Accordingly, allopregnanolone caused an increase in the slow decay time constant of spontaneous GABA-mediated IPSCs in magnocellular neurons recorded in hypothalamic slices. The allopregnanolone effect on IPSCs was inhibited by a G-protein antagonist as well as by blocking protein kinase C and, to a lesser extent, cAMP-dependent protein kinase activities. G-protein and protein kinase C activation in the absence of the neurosteroid had no effect on spontaneous IPSCs but enhanced the effect of subsequent allopregnanolone application. These findings together suggest that the neurosteroid modulation of GABA-mediated IPSCs requires G-protein and protein kinase activation, although not via a separate G-protein-coupled steroid receptor.

Animals↗
PubMed1992

Regional variation in steroid anesthetic modulation of [35S]TBPS binding to gamma-aminobutyric acidA receptors in rat brain.

Steroids that enhance gamma-aminobutyric acid (GABA)A receptor function in the central nervous system allosterically modulate the binding of the convulsant chloride channel ligand [35S]-t-butyl bicyclophosphorothionate. When assayed in membrane homogenates and in tissue sections by autoradiography, concentration-dependence curves vary with respect to both brain region and the nature of the steroid. Alphaxalone and endogenous steroid hormone metabolites inhibit the binding of [35S]-t-butyl bicyclophosphorothionate in some regions, enhance it in others and give biphasic concentration-dependence in others, apparently the result of algebraic summation of two effects involving regional-dependent enhancement or inhibition. The alphaxalone effect is additive with that produced by adding GABA to the binding assays in some regions, but synergistic in other areas. Likewise, the effect of GABA is inhibited completely by saturating concentrations of the antagonist bicuculline methochloride in some areas but only partially in others, and completely or partially reversed by the convulsant benzodiazepine Ro5-4864, depending on region. The granule cell and molecular layers of cerebellum are particularly different in these allosteric interactions. The heterogeneity of binding behavior is consistent with the presence of multiple GABAA receptor subtypes in the brain. Regional variation in subunit gene expression apparently produces a family of hetero-oligomeric GABAA receptors with different biological and pharmacological properties, including qualitative and quantitative differences in modulation by neuroactive steroids.

Anesthetics↗
PubMed1997

Lactone modulation of the gamma-aminobutyric acid A receptor: evidence for a positive modulatory site.

The gamma-aminobutyric acid-A (GABA(A)) receptor complex is allosterically modulated by a variety of substances, some of clinical importance. Barbiturates and neurosteroids augment GABA-currents and also directly gate the channel. A variety of gamma-butyrolactone analogues also modulate GABA-induced currents, with some potentiating and others inhibiting. Because several gamma-thiobutyrolactone analogues have biphasic effects on GABA currents, experiments with wild-type and picrotoxinin-insensitive GABA(A) receptors were performed to analyze whether some gamma-thiobutyrolactones interact with two distinguishable sites on the GABA(A) receptor. beta-Ethyl-beta-methyl-gamma-thiobutyrolactone inhibited GABA-induced currents at low concentrations (0.001-1 mM), but potentiated GABA-induced currents at higher concentrations (3-10 mM) in wild-type alpha1beta2gamma2-subunit containing ionophores. The related alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone potentiated submaximal GABA currents in wild-type receptors at both low and high concentrations (0.1-10 mM). Mutations in the second transmembrane domain of alpha1, beta2, or gamma2 conferred picrotoxinin-insensitivity onto GABA(A) receptor complexes. When these mutated alpha1, beta2, or gamma2 subunits were incorporated into the receptor complex, beta-ethyl-beta-methyl-gamma-thiobutyrolactone potentiated GABA currents over the entire concentration range (0.1-10 mM). Neither the potentiating activity nor the EC50 of alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone changed in the mutant receptors. Further studies demonstrated that the mutations did not affect the EC50 of chlordiazepoxide or phenobarbital. These and our earlier results identify a modulatory site on the GABA(A) receptor distinct from that interacting with barbiturates, benzodiazepines, and steroids. Additionally, they show that the gamma-butyrolactones probably interact at two different sites on the ionophore to produce opposite effects on GABA-mediated current.

4-Butyrolactone↗
PubMed2003

Pharmacology of endogenous neuroactive steroids.

Neuroactive steroids are potent endogenous neuromodulators with rapid actions in the central nervous system. Neuroactive steroids have been claimed to have specific physiological roles in normal or pathological brain function. This article reviews the emerging evidence that progesterone-, deoxycorticosterone-, and testosterone-derived endogenous neuroactive steroids play an important role in the modulation of neural excitability and brain function. Neuroactive steroids such as allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) are extremely potent positive allosteric modulators of GABAA receptors with sedative, anxiolytic, and anticonvulsant properties. The sulfated neuroactive steroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), which are negative GABAA receptor modulators, induce anxiogenic and proconvulsant effects. Thus, natural fluctuations in neuroactive steroid levels during the menstrual cycle and stress could affect several nervous system functions. There is strong evidence that allopregnanolone and THDOC are involved in the pathophysiology of premenstrual syndrome, catamenial epilepsy, major depression, and stress-sensitive brain disorders. Neuroactive steroids PS and DHEAS have been shown to modulate memory functions. However, the significance of the testosterone-derived neuroactive steroid 3alpha-androstanediol is not well understood. Like naturally occurring neuroactive steroids, synthetic derivatives such as ganaxolone have been proven in preclinical and clinical studies to be effective anticonvulsants with great potential for human use. Future research on inhibition or stimulation of specific neuroactive steroid synthesizing enzymes could provide an improved understanding and novel approaches for the treatment of anxiety, epilepsy, and depression.

Animals↗
PubMed2026

Structure-Function Analysis of the Benzyloxy Moiety of the Delta-Opioid Receptor Positive Modulator BMS-986187: Identification of a Derivative with High Selectivity for the Delta-Opioid Receptor over the Mu-Opioid Receptor In Vitro and In Vivo.

Positive allosteric modulators (PAMs) of the delta-opioid receptor (DOR) enhance endogenous opioid signaling while avoiding the convulsant liability of orthosteric agonists. However, the prototypical DOR-PAM, BMS-986187, also potentiates mu-opioid receptor (MOR) signaling, raising concerns regarding respiratory depression and abuse liability. Here, we report a structure-activity study of the benzyloxy moiety of BMS-986187 to improve selectivity for DOR over MOR, while retaining DOR-PAM potency. Fifty-two new analogues and 12 previously reported ones featuring mono- and disubstitution of the benzyl ring and phenyl-heterocycle replacements were synthesized and evaluated in β-arrestin2 recruitment assays. Ortho-substituted derivatives consistently enhanced DOR-PAM potency, although often increased MOR-PAM activity. One pyridyl derivative (compound 35) retained high DOR-PAM potency and efficacy (EC50 = 0.1 μM, Emax = 91%) with no detectable MOR activity. In mice, compound 35 enhanced DOR-mediated reversal of nitroglycerin-induced hyperalgesia, an effect absent in DOR-knockout mice, without enhancing MOR-mediated antinociception, demonstrating in vivo selectivity.

Receptors, Opioid, delta↗
PubMed2000

Regulation of the type III InsP(3) receptor by InsP(3) and ATP.

Many hormones and neurotransmitters raise intracellular calcium (Ca(2+)) by generating InsP(3) and activating the inositol 1,4, 5-trisphosphate receptor (InsP(3)R). Multiple isoforms with distinct InsP(3) binding properties () have been identified (). The type III InsP(3)R lacks Ca(2+)-dependent inhibition, a property that makes it ideal for signal initiation (). Regulation of the type III InsP(3)R by InsP(3) and ATP was explored in detail using planar lipid bilayers. In comparison to the type I InsP(3)R, the type III InsP(3)R required a higher concentration of InsP(3) to reach maximal channel activity (EC(50) of 3.2 microM versus 0.5 microM for the types III and I InsP(3)R, respectively). However, the type III InsP(3)R did reach a 2.5-fold higher level of activity. Although activation by InsP(3) was isoform-specific, regulation by ATP was similar for both isoforms. In the presence of 2 microM InsP(3), low ATP concentrations (<6 mM) increased the open probability and mean open time. High ATP concentrations (>6 mM) decreased channel activity. These results illustrate the complex nature of type III InsP(3)R regulation. Enhanced channel activity in the presence of high InsP(3) may be important during periods of prolonged stimulation, whereas allosteric modulation by ATP may help to modulate intracellular Ca(2+) signaling.

Adenosine Triphosphate↗
PubMed2005

Neuroactive steroids as modulators of depression and anxiety.

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the GABA type A-receptor. During major depression there is a dysequilibrium of 3alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment we studied the impact of non-pharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder changes in neuroactive steroid composition have been observed opposite of those seen in depression. These changes may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimental panic induction with either cholecystokinin-tetrapeptide or sodium lactate there was a pronounced decline in the concentrations of 3alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3alpha, 5alpha-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone. The modulation of GABA type A-receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.

Animals↗
PubMed1998

Chronic dizocilpine (MK-801) reversibly delays GABA(A) receptor maturation in cerebellar granule neurons in vitro.

We investigated the effect of chronically blocking NMDA receptor stimulation to examine changes in GABA(A) receptor expression and pharmacology in cerebellar granule cells at different stages of maturation. We have previously shown that NMDA-selective glutamate receptor stimulation alters GABA(A) receptor pharmacology in cerebellar granule neurons in vitro by altering the levels of selective subunits. When NMDA receptor stimulation is blocked with MK-801 during the first week in vitro, a decrease in the alpha1, gamma2S, and gamma2L receptor subunit mRNAs occurred. When present only during the second week, changes were limited to the alpha1 and gamma2L mRNAs. Finally, if MK-801 was present during the first week and removed during the second week, these changes reversed. Whole-cell voltage-clamp recordings showed that treatment with MK-801 during either the first or second week increased the EC50 of the receptors for GABA and attenuated the potentiation mediated by flunitrazepam. Last, these properties were reversed if MK-801 was removed after the first week in vitro. Our results suggest that MK-801 reversibly inhibits GABA(A) receptor maturation by modulating receptor subunit expression and that the altered pharmacological responses appear to be dominated by changes in the levels of allosteric modulation mediated by the gamma2 receptor subunit.

Animals↗
PubMed2006

Neuroactive steroids in depression and anxiety disorders: clinical studies.

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium of 3alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3alpha,5alpha-tetrahydrodeoxycorticosterone. The modulation of GABA(A) receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.

Animals↗
PubMed1990

[GABA(A) benzodiazepine receptors and epilepsy].

GABAA-benzodiazepine receptors and epilepsy. gamma-Aminobutyric acid (GABA) is quantitatively one of the most important neurotransmitters in the central nervous system. Since the predominant action of GABA on neurons is inhibitory, activation of GABA receptors, and especially of GABAA receptors, causes an anticonvulsive effect. GABAA receptors can be activated either directly by GABA or GABA-agonists, or indirectly by allosteric modulation of these receptors. For instance, benzodiazepines enhance the postsynaptic actions of GABA by binding to benzodiazepine receptors which are allosteric modulatory binding sites on GABAA receptors. Conversely, there are compounds which bind to the same benzodiazepine receptors, but reduce the postsynaptic actions of GABA. These compounds cause convulsions and are called "inverse agonists" of the benzodiazepine receptors. Recent evidence indicates the existence of several different benzodiazepine receptor (and, thus, GABAA receptor) subtypes. Since these receptor subtypes exhibit a different regional distribution in the central nervous system, the development of subtype-selective GABAA receptor agonists or benzodiazepine receptor agonists should result in anticonvulsants with less side effects.

Animals↗
PubMed2005

Subtype-selective noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1).

This article describes recent advances in the development of subtype-selective, noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1). mGluR1 plays an important role in modulating synaptic transmission and neuronal excitability via intracellular signal transduction pathways and has been implicated in a number of CNS disorders. Allosteric modulation of mGluR1 by potentiation and antagonism occurs through binding to the seven transmembrane domain. In addition to blocking agonist-dependent responses, many of the antagonists also show inverse-agonist activity by blocking constitutive receptor activity. Highly potent and selective mGluR1 radioligands have been used to evaluate receptor binding in vivo and in vitro. Some of these novel agents have demonstrated high levels of CNS exposure and receptor occupancy in vivo, as well as efficacy in a number of preclinical models of neurological disorders.

Allosteric Regulation↗
PubMed2000

Natural and synthetic polyamines: modulators of signalling proteins.

Ionotropic receptors are modulated allosterically by natural polyamines, such as spermine, and by polyamine derivatives, such as polyamine amides (e.g. philanthotoxin-343) and polymethylene tetraamines (e.g. methoctramine. Modulation can be either positive (potentiation) or negative (non-competitive antagonism of either open or closed channel receptor conformation). Photoaffinity labelling studies have identified a site close to the channel lumen on the nicotinic acetylcholine receptor Torpedo electroplax that is probably the allosteric site responsible for antagonism of the closed channel conformation of this receptor.

Animals↗
PubMed2001

Modulation of haemocyanin oxygen affinity: properties and physiological implications in a changing world.

Crustacean haemocyanin oxygen affinity may be modified through changes in concentration of various inorganic and organic allosteric modulators. These may act in both positive and negative directions, increasing or decreasing haemocyanin oxygen affinity, and assist both in oxygen loading at the gills and oxygen release in the tissues. Inorganic ions, except for Mg(2+), do not normally influence cooperativity or the Bohr effect, whereas most of the organic modulators decrease cooperativity without affecting the Bohr coefficient. Several new findings on the influence of sulphide and thiosulphate are reviewed together with evidence for unidentified factors that decrease haemocyanin oxygen affinity. The physiological implications of all these findings are discussed in the context of maintaining a flexible response to a changing environment.

Animals↗
PubMed1992

1,3-Di(2-[5-3H]tolyl)guanidine labels more than one site in rat forebrain.

Studies of 1,3-di-(2-[5-3H]tolyl)guanidine ([3H]DTG) binding to rat brain membranes revealed that [3H]DTG binds to a high and a low affinity site with Kd values of 19.8 nM and 1.31 microM (corresponding Bmax values 291 fmol/mg protein and 8.68 pmol/mg protein). The order of potency of competitors for [3H]DTG binding revealed a binding profile typical of sigma site ligands. Several sigma ligands such as the enantiomers of 3-PPP (3-(3-hydroxyphenyl)-N- (n-propyl)piperidine) and (+/-)-pentazocine exhibited biphasic competition profiles for [3H]DTG binding, whereas other sigma ligands such as haloperidol displayed monotonic competition curves. Neither phenytoin nor carbamazepine were observed to enhance [3H]DTG binding. These data support the hypothesis that multiple sigma binding sites exist. The lack of phenytoin and carbamazepine modulation of [3H]DTG binding are in agreement with the proposed greater density of sigma site 2 in the rat, since allosteric modulation has been ascribed to the DM1/sigma 1 site.

Animals↗