Involvement of the sigma1 (sigma1) receptor in the anti-amnesic, but not antidepressant-like, effects of the aminotetrahydrofuran derivative ANAVEX1-41.

BACKGROUND AND PURPOSE: Tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41) is a potent muscarinic and sigma(1) (sigma (1)) receptor ligand. The sigma (1) receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti-amnesic and antidepressant DRUGS. WE HAVE HERE ANALYSED THE SIGMA (1) COMPONENT IN THE BEHAVIOURAL EFFECTS OF ANAVEX1-41. EXPERIMENTAL APPROACH: Binding of ANAVEX1-41 to muscarinic and sigma (1) receptors were measured using cell membranes. Behavioural effects of ANAVEX1-41 were tested in mice using memory (spontaneous alternation, passive avoidance, water-maze) and antidepressant-like activity (forced swimming) procedures. KEY RESULTS: In vitro, ANAVEX1-41 was a potent muscarinic (M(1)>M(3), M(4)>M(2) with K(i) ranging from 18 to 114 nM) and selective sigma (1) ligand (sigma (1), K(i)=44 nM; sigma (2), K(i)=4 microM). In mice, ANAVEX1-41 failed to affect learning when injected alone (0.03-1 mg kg(-1)), but attenuated scopolamine-induced amnesia with a bell-shaped dose response (maximum at 0.1 mg kg(-1)). The sigma (1) antagonist BD1047 blocked the anti-amnesic effect of ANAVEX1-41 on both short- and long-term memories. Pretreatment with a sigma (1) receptor-directed antisense oligodeoxynucleotide prevented effects of ANAVEX1-41 only in the passive avoidance procedure, measuring long-term memory. ANAVEX1-41 reduced behavioural despair at 30 and 60 mg kg(-1), without involving the sigma (1) receptor, as it was not blocked by BD1047 or the antisense oligodeoxynucleotide. CONCLUSIONS AND IMPLICATIONS: ANAVEX1-41 is a potent anti-amnesic drug, acting through muscarinic and sigma (1) receptors. The latter component may be involved in the enhancing effects of the drug on long-term memory processes.

[Action mechanism of anticonvulsant and anti-immobility (forced swim) effects of 3', 4'-dihydro-N, N-dimethylspiro-[9H-fluorene-9, 2' (5'H) furane]-3'-methanamine (AE37F)]. / Mécanisme d'action des effects anticonvulsivant et anti-immobilité (nage forcée) de la 3, 4'-dihydro-N,N-diméthylspiro [9H-fluorène-9,2' (5'H)-furane]-3'-méthanamine (AE37F).

AE37F, a new aminotetrahydrofuranic derivative, exhibited, at 10-30 mg/Kg (po) or 1-10 mg/Kg (ip), antagonism of tonic convulsions, induced by pentetrazole (130 mg/Kg, ip), and of forced swin immobility, in mice. At these doses AE37F induced a considerable (100-250%) increase of serotonin (5-HT) and its main metabolite, 5-hydroxyindolacetic acid (5-HIAA), in the rat nucleus reticularis pontis oralis (NRPO), antagonized by amantadine, which also increased 5-HT and 5-HIAA levels in the NRPO. It is suggested: a) that the anti-immobility effect of AE37F is related to its antimuscarinic properties, b) that the rate of 5-HT release in the NRPO, calculated here by a new approach (from the 5-HT and 5-HIAA brain levels) is increased by AE37F and decreased by amantadine, in the NRPO, c) that the anti-convulsant action, observed with AE37F, could be related to a NMDA-sigma mediated stimulation of serotoninergic, GABAergic and glycinergic brain neurones, antagonized by the NMDA-sigma inhibition induced by amantadine.

[Selective M1 muscarinic agonists: failure of therapeutic strategy against Alzheimer's disease or inappropriate tactics?]. / Agonistes muscariniques sélectifs M1: échec d'une stratégie thérapeutique contre la maladie d'Alzheimer ou tactique inappropriée?

Clinical trials of selective M1 muscarinic agonists against Alzheimer's disease (AD) were, except perhaps for xanomeline, decevant. However, the strategy sustaining the conception of these agonists was rational: based on the high densities of post-synaptic M1 and M2/M3 receptors, respectively, in the brain (cortex, hippocampus) and periphery as well as on the preservation of M1 receptors in the AD. However, most of the clinically tested M1 agonists exhibited low (but suffisant for pre-synaptic M2 autoreceptors and M3 heteroreceptors on the glutamatergic terminals) M2/M3 agonisms, susceptible to annul their M1 agonism. The rest of these agonists, developed a M1 agonism too weak, susceptible to operate as functional antagonism in the cholinergic synapses. In conclusion, it appeared that the efficacy of the M1 agonists against AD must be tested with full M1 agonists being also net M2/M3 antagonists, a profile recently evidenced with tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanemethanamine (AE14).

[Anticonvulsant and forced swim anti-immobility effects of tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanemethanamine (AE37): common action mechanism?]. / Effets anticonvulsivant et anti-immobilité (nage forcée) de la tétrahydro-N, N-diméthyl-2, 2-diphényl-3-furaneméthanamine (AE37).

Tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanemethanamine (AE 37) is a newly synthesized anticonvulsant drug efficient against electrogenic (maximal electroshock: MES) or pentetrazole (PTZ) induced tonic convulsions of mice. It also antagonizes the immobility of adult or aged mice in the forced swim test (FST), which is used to detect antidepressive properties. Neurochemical changes induced by AE37 (antagonistic action on the sodium channel currents and on the receptors sensitive to N-methyl-D-aspartic acid) could generate the aforementioned pharmacological properties, whereas the partial agonistic action of AE 37 on the brain muscarinic receptors seems to confer to this drug characteristics of third generation antiepileptic.

[Mechanism of action of tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanemethanamine, a putative nootropic, anti-epileptic and antidepressant compound]. / Mécanisme d'action de la tétrahydro-N, N-diméthyl-5, 5-diphényl-3-furaneméthanamine, un dérivé potentiellement nootrope, antiépileptique et antidépresseur.

Pharmacological studies on tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanemethanamine (AE14) pointed out its prominent action in the passive avoidance test, its antagonist effect on electrogenic (maximal electroshock, MES) or pentetrazole-induced tonic convulsions, and its anti-immobility effect in the forced swim test (FST) in mice. These pharmacological data suggest that AE14 could exhibit nootropic, antiepileptic and antidepressant actions. Molecular pharmacology studies (receptology, bioresponse) with AE14 showed a selective M1 muscarinic agonism, one of the most potent currently known, and an affinity for site 2 of the sodium ion channels, at least as strong as those of first or second generation antiepileptics (phenytoin, lamotrigine). These molecular effects show that AE14 could be a potential second generation anti-Alzheimer drug, a third generation antiepileptic, and an adjunct for antidepressants.

[Effect of amantadine or 3-cyclopentyl adamantanamine on the immobility of adult or aged mice, in the forced swim test]. / Effet de l'amantadine ou de la 3-cyclopentyl adamantanamine sur l'immobilité des souris adultes ou âgées, au test de la nage forcée.

Amantadine (AMA), an antiparkinsonian drug, (20 mg/Kg, ip) or 3-cyclopentyl adamantanamine (AdCP), an AMA derivative synthesized recently, (20 mg/Kg, ip) induced an anti-immobility effect-comparable to those of imipramine (IMI), an antidepressive drug, (30 mg/Kg, ip) - in the forced swim test (FST), on adult (4 months) Balb-C mice. In contrast, on aged (10 months) Balb-C mice, only AdCP (20 or 40 mg/Kg, ip) was active in the FST. It is suggested that the inactivity of AMA or IMI on the aged Balb-C mice could be the consequence of their NMDA (i.e., N-methyl-D-aspartic acid sensitive) receptors failure. This NMDA receptors dysfunction could render non significant the antagonism of the mice immobility in the FST, induced by AMA or IMI, which could result (in part for IMI) from the anti-NMDA effect of these drugs. In contrast AdCP, which may principally act by glycinergic A (strychnine sensitive) effect, inhibiting the release of the brain monoamines and glutamate, conserved its activity in the FST on aged mice. In conclusion, it seems that the neurochemical profile of the drugs studied in the FST, could be useful for understanding their anti-immobility effect and for a rational approach of their possible clinical use as antidepressant.

[Effect of presynaptic dopaminergic agonism on the immobility of mice in the forced swimming test]. / Effet de l'agonisme dopaminergique présynaptique sur l'immobilité des souris dans le test de la nage forcée.

Administration of 0.05 mg/kg (i.p.) of apomorphine (APO) or of the two dopamine (DA) lipoamides, DA steatamide (S-DA) or DA palmitamide (P-DA), at doses of 10 or 30 mg/kg (i.p.), induced an anti-immobility effect, in the forced swimming test in mice, of the same order as those of imipramime (30 mg/kg, i.p.). At the aforementioned doses APO, S-DA or P-DA could be acting on the dopaminergic autoreceptors and cause a decrease of the turnover and/or the release of the brain DA in the striatum. In contrast, DA linoleamide (L-DA), which has no action on the brain DA, did not exhibit anti-immobility effect. It is suggested that the decrease of turnover and/or release of the brain DA, induced by APO, S-DA or P-DA, could constitute a clue of the extent of the extrasynaptic action developed by these drugs whose antiglutamatergic incidence could cause the anti-immobility effect, observed with these derivatives, as well as their possible antidepressive action.

[D-cycloserine is active in the adult mouse and inactive in the aged mouse, in the forced swim test]. / La D-cyclosérine est active chez la Souris adulte et inactive chez la Souris âgée, dans le test de la nage forcée.

The glycinergic site agonist of the NMDA receptors, D-cycloserine (DCS), exhibit an anti-immobility effect in the forced swim (FS) test, on adult mice. This effect, predicting antidepressive properties, is of the same order as those of imipramine (IMI). In constrast, DCS and IMI did not exhibited any significant anti-immobility effect on aged mice (12 months). IMI being active, in the depression of aged persons, it seems that the FS test has not any predictive value concerning the action of antidepressant drugs on aged persons. On the other hand Gabalid, a mixed (A, B) GABAergic agonist, AE37, a partial muscarinic agonist and N-linoleyl glycine, a mixed (A, B) glycinergic agonists, are active, in the FS test, on adult as well on aged mice. Mixed (A, B) glycinergic agonist, Gabalid or AE37 and, generally, partial muscarinic agonists, are active on the passive avoidance test (step-down) on mice, which predict nootropic effects. These results, considered in relation with recent data on the impact of FS or functional inhibition (GABAergic, glycinergic A, antimuscarinic) of glutamatergic neurons on the glycinergic modulation of the NMDA receptors, could suggest that the FS test on aged mice could possess a predictive value for nootropic rather than for antidepressant drugs.

[Spongiform encephalopathies: a second chance for GABAergic agonists]. / Encéphalopathies spongiformes: une deuxième chance pour les agonistes GABAergiques?

The risk of transmission of bovine spongiform encephalopathy (BSE) to humans and of a possible emergence, in the future, of an epidemic being seriously envisaged, a detection of the infection by the BSE prions is at present going well. On the other hand, recent neurochemical studies could suggest the triggering of an overstimulation of the brain GABAergic and glutamatergic systems after infection by the BSE prions. This overstimulation could, in the long-term (latency between the infection and the emergence of the clinical signs of the disease), lead to the destruction of the major inhibiting system (GABAergic) of the brain and the generalization of the neurotoxic processes. According to the above mentioned working hypothesis, it could be envisaged to use, immediately after the detection of the infection by the BSE prions, mixed GABAergic (A, B) agonists, selectively acting on the GABAergic autoreceptors and on the heteroreceptors situated on the glutamatergic terminals. Moreover these agonists could exhibit molecular characteristics (in terms of lipophilicity), which could operate in order to prevent the fixation of prions on the neuronal and astroglial membranes allowing their multiplication. According to the above mentioned criteria, mixed agonists Progabide and Gabalid or some GABA (B) agonists, with a relatively low affinity, could, actually, be the most interesting.

Synthesis, lipophilicity and biological evaluation of indole-containing derivatives of 1,3,4-thiadiazole and 1,2, 4-triazole.

3-[(2-Methyl-1H-3-indolyl) methyl]-4-aryl-4, 5-dihydro-1H-1,2,4-triazole-5-thiones 6a-c and their respective N-¿5-[2-methyl-1H-3-indolyl) methyl]-1,3,4-thiadiazol-2-yl¿-N-arylamines 7a,b have been prepared. The antidepressant profile of 6a,c and 7a was studied on mice with respect to that of the analogous 3-(1H-1-indolylmethyl)-4-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thio nes 1a-c and the respective N-¿5-[(2-methyl-1H-3-indolyl) methyl]-1,3,4-thiadiazole-2-yl¿-N-arylamines 2a-c, the synthesis and antimicrobial potency of which we have recently reported. Behavioral effects, induced by the members of both series, in conjunction with their activity in some specific tests (forced swim, pentetrazole convulsions) on mice, show that these derivatives cross the blood-brain barrier and could develop an antidepressant activity comparable to that of imipramine. Blood-brain barrier penetration is also supported by the lipophilicity data obtained for all analogs.

[Chronic treatment with tween-80 (5%) or n-stearoyl glycine on the antimobility effects of imipramine in the forced swimming test in mice]. / Le traitement chronique par le Tween-80 (5%) n'affecte pas l'effect antiimmobilité de la N-stéaroyl glycine, mais supprime celui de l'Imipramine, au test de la nage forcée chez la souris.

Chronic (7 days) administration of N-stearoyl glycine (SG) or Tween-80 (5%) suppress the antiimmobility effect of Imipramine, in the forced swimming test on mice, whereas the antiimmobility effect of SG is suppressed only after chronic treatment with SG. These results suggest that chronic SG treatment could desensitize the glycinergic site of the NMDA receptors and that chronic Tween-80 (5%) administration could inactivate the glutamatergic site of the NMDA receptors or disturb some modulation, other than glycinergic, of the NMDA ionic channel. The latter could be important in an environmental or experimental viewpoint.

The neurochemical effects on striatal dopamine turnover rate of N-stearyl dopamine after acute administration in rats.

1. Considerable efforts have been made in order to develop autoreceptor selective agonists for the treatment of schizophrenia and hyperkinetic disorders. 2. Recent behavioural studies showed that the newly synthesized dopamine lipoamide, N-stearyl dopamine induced a strong hypomotility (-80%) in rats and mice. It is worth noting that this behavioural response was partially antagonized by dopaminergic antagonists, such as haloperidol and sulpiride, administered at doses that block DA autoreceptors. 3. In the present study the authors investigated the neurochemical changes induced by S-DA, in the striatum of the rat brain, in order to estimate a possible correlation between the above mentioned behavioural response and DA metabolism. 4. S-DA (10 or 100 mg/kg, i.p.) induced a significant decrease in DA turnover rate while it did not affect 5-HT metabolism in the striatum. 5. Considering that 5-DA induces a strong hypomotility, which can be partially antagonized by haloperidol or sulpiride administered at low doses, while also decreases the striatal DA turnover rate, it could be suggested that together these findings indicate that this DA lipoamide may be display the characteristics of an antipsychotic agent, acting on the "DA selective" autoreceptors.

Synthesis and pharmacological study of some new beta-(dialkylaminomethyl)- gamma-butyrolactones and their tetrahydrofuran analogues.

This paper describes the synthesis of beta-(dialkylaminomethyl)-gamma- butyrolactones (6 and 15) and their tetrahydrofuran analogs 7 and 16. Their convulsant activity was studied on mice and could display an antiGABAergic component, but, unlike the alpha-(dialkylaminomethyl)- gamma-butyrolactones, no antiglycinergic component was detected. The possibility of an activation of the glutamatergic receptors (NMDA), by indirect stimulation of their glycinergic site, by the tetrahydrofurans analogs 7 could be considered. These compounds exhibited, at low doses (1/3 to 1/20 of their convulsant doses), an anticonvulsant action in the maximal electroshock test and this is in agreement with the abovementioned possibility.

[Inactivity of imipramine in the forced swimming test on old mice or on young mice undergone chronic glycinergic treatment]. / Inactivité de l'imipramine dans le test de la nage forcée chez les souris âgées ou chez de jeunes souris soumises à un traitement glycinergique chronique.

Balb-C old (10 or 12 months) mice were submitted to the forced swimming test (FST) after treatment by imipramine (IMI) or by glycinergic A agonists (which operate on the strychnine sensitive receptors). The latter, but not IMI, exhibited an anti-immobility effect, predicting an antidepressive activity, in the FST. The same results were obtained with young mice (4 months) having undergone, 48 hours before the administration of IMI or N-linoleyl glycine (glycinergic A) or D-cycloserine (glycinergic B), a chronic (7 days) glycinergic A or B (acting on the strychnine insensitive receptors) treatment. These results could confirm the recent theories on the anti-NMDA effects of acutely or chronically administered IMI and could raise some interesting questions about the possible antidepressive activity of glycinergic A agonists.

[Pharmacologic profile of n-palmitoylglycine. Its effect on reserpine and haloperidol catalepsy]. / Profil pharmacologique de la N-palmitoyl glycine. Etude de son effet sur la catalepsie à la réserpine ou à l'halopéridol.

N-palmitoyl glycine (PG), synthesized by the mixed anhydrides method, displayed nootropic effects (in the "step-down" test) as well as an anti-immobility action in the forced swimming test, in mice. However no anticonvulsant effects were obtained, even at high dose (300 mg/Kg, po), in the maximal electroshock or against the convulsions induced by pentetrazol. In the study reported in this paper PG potentiated the reserpine or the haloperidol catalepsy in rats. The potentiation of the haloperidol catalepsy was antagonized by imipramine which displayed antiglutamatergic and antimuscarinic properties. On the other hand at 150 mg/Kg (ip), a dose which potentiated the haloperidol catalepsy, PG stimulated the dopaminergic function in the striatum. These results could therefore constitute a first clue suggesting a stimulation, by PG, of the cholinergic and GABAergic interneurons, by glycinergic potentiation of the NMDA receptors in the striatum.

[Synthesis and pharmacological study of adamantyl benzene propanamines and propenamines]. / Synthèse et étude pharmacologique des adamantylbenzènepropanamines et propénamines.

gamma-(1-Adamantyl)benzenepropanamines and gamma-(1-adamantyl)benzene-beta-propenamines were synthesized and their pharmacological action was studied on mice. Behavioral effects obtained with these compounds and specially the study of convulsions, induced by these derivatives, could show a rise of the gamma-(1-adamantyl)benzenepropanamine's antinicotinic component, which is characteristic of all the adamantanamines. On the contrary gamma-(1-adamantyl)benzene-beta-propenamine's molecular torsion, induced by the double bond, coudl confer to these derivatives agonistic properties on the central nicotinic receptor sites.

3-Cyclopentyl-1-adamantanamines and adamantanemethanamines. Antiviral activity evaluation and convulsions studies.

The synthesis of 3-cyclopentyl-1-adamantanamines and adamantanemethanamines and some of their thioureas is described. The antiviral activity examination of these compounds indicated that some of them inhibited Respiratory Syncytial Virus (RSV) infection at concentrations that were slightly (up to 5-fold) lower than the cytotoxic concentration. Behavioral and convulsions studies of the above mentioned amines, in mice, did not show any dopaminomimetic activity and argue in favor of the existence of a glutamatergic component in the action of these derivatives.

[The mechanism(s) of alpha-(aminoethyl)-gamma-butyrolactone. In vivo studies in mice]. / Les mechanisme(s) d'une a-(aminoéthyl)-gamma butyrolactone. Etudes in vivo chez la souris.

This paper describes the synthesis of alpha-(dimethylaminoethyl)-gamma, gamma-diphenyl-gamma-butyrolactone 4. The study of convulsions induced, on mice, by this compound could show the existence of antiGABAergic and cholinergic action components, but, unlike the homologous alpha- (dialkylaminomethil)-gamma-butyrolactones (with one -CH2- less on the aminoalkyl chain), no antiglycinergic component was detected. The effects of atropine on the aminolactone 4 induced convulsions (antagonism 5mn and synergy 30 mn after atropine) could suggest an activation of the glutamatergic receptors (NMDA), by indirect stimulation of their glycinergic site, by the aminolactone 4.