Steinberg R

References (8)

Title : SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (II) efficacy in experimental models predictive of activity against cognitive symptoms of schizophrenia - Pichat_2007_Neuropsychopharmacology_32_17
Author(s) : Pichat P , Bergis OE , Terranova JP , Urani A , Duarte C , Santucci V , Gueudet C , Voltz C , Steinberg R , Stemmelin J , Oury-Donat F , Avenet P , Griebel G , Scatton B
Ref : Neuropsychopharmacology , 32 :17 , 2007
Abstract : SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective alpha7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the alpha7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801- or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective alpha7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.
ESTHER : Pichat_2007_Neuropsychopharmacology_32_17
PubMedSearch : Pichat_2007_Neuropsychopharmacology_32_17
PubMedID: 16936709

Title : SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile - Biton_2007_Neuropsychopharmacology_32_1
Author(s) : Biton B , Bergis OE , Galli F , Nedelec A , Lochead AW , Jegham S , Godet D , Lanneau C , Santamaria R , Chesney F , Leonardon J , Granger P , Debono MW , Bohme GA , Sgard F , Besnard F , Graham D , Coste A , Oblin A , Curet O , Vige X , Voltz C , Rouquier L , Souilhac J , Santucci V , Gueudet C , Francon D , Steinberg R , Griebel G , Oury-Donat F , George P , Avenet P , Scatton B
Ref : Neuropsychopharmacology , 32 :1 , 2007
Abstract : In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
ESTHER : Biton_2007_Neuropsychopharmacology_32_1
PubMedSearch : Biton_2007_Neuropsychopharmacology_32_1
PubMedID: 17019409

Title : Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic - Depoortere_2005_Neuropsychopharmacology_30_1963
Author(s) : Depoortere R , Dargazanli G , Estenne-Bouhtou G , Coste A , Lanneau C , Desvignes C , Poncelet M , Heaulme M , Santucci V , Decobert M , Cudennec A , Voltz C , Boulay D , Terranova JP , Stemmelin J , Roger P , Marabout B , Sevrin M , Vige X , Biton B , Steinberg R , Francon D , Alonso R , Avenet P , Oury-Donat F , Perrault G , Griebel G , George P , Soubrie P , Scatton B
Ref : Neuropsychopharmacology , 30 :1963 , 2005
Abstract : Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
ESTHER : Depoortere_2005_Neuropsychopharmacology_30_1963
PubMedSearch : Depoortere_2005_Neuropsychopharmacology_30_1963
PubMedID: 15956994

Title : 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylp henyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization - Gully_2002_J.Pharmacol.Exp.Ther_301_322
Author(s) : Gully D , Geslin M , Serva L , Fontaine E , Roger P , Lair C , Darre V , Marcy C , Rouby PE , Simiand J , Guitard J , Gout G , Steinberg R , Rodier D , Griebel G , Soubrie P , Pascal M , Pruss R , Scatton B , Maffrand JP , Le Fur G
Ref : Journal of Pharmacology & Experimental Therapeutics , 301 :322 , 2002
Abstract : 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.
ESTHER : Gully_2002_J.Pharmacol.Exp.Ther_301_322
PubMedSearch : Gully_2002_J.Pharmacol.Exp.Ther_301_322
PubMedID: 11907190

Title : SR 46559A: a novel and potent muscarinic compound with no cholinergic syndrome - Kan_1993_Psychopharmacology_112_219
Author(s) : Kan JP , Steinberg R , Oury-Donat F , Michaud JC , Thurneyssen O , Terranova JP , Gueudet C , Souilhac J , Brodin R , Boigegrain R , et al.
Ref : Psychopharmacology , 112 :219 , 1993
Abstract : The cholinergic activities of SR 46559A, 3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki = 112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6-7 times lower. SR 46559A did not interact with brain nicotinic receptors and high affinity choline uptake sites nor did it inhibit brain acetylcholinesterase activity. In contrast to reference muscarinic agonists, SR 46559A (1 mM) did not inhibit the forskolin-induced activation of cAMP synthesis nor did it stimulate phosphoinositides breakdown in various brain preparations. However, this compound enhanced (+67% at 1 mM) diacylglycerol formation in rat striatal miniprisms, an effect fully reversed by atropine. As shown with reference agonists, SR 46559A inhibited (IC50 = 10 microM) the K(+)-evoked release of [3H]GABA from rat striatal slices and reduced at 0.5 and 1 microM, the population spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffer's collateral commissural pathway in rat hippocampal slices. In mice, SR 46559A at a near lethal dose (200 mg/kg PO) did not induce the typical cholinergic syndrome nor did it modify at 30 mg/kg PO the oxotremorine-induced hypothermia. Like muscarinic agonists, SR 46559A (1 mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50 = 0.12 mg/kg PO) rotations induced in mice by intrastriatal injection of pirenzepine.
ESTHER : Kan_1993_Psychopharmacology_112_219
PubMedSearch : Kan_1993_Psychopharmacology_112_219
PubMedID: 7871023

Title : Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates - Fournier_1993_Neurosci_55_629
Author(s) : Fournier J , Steinberg R , Gauthier T , Keane PE , Guzzi U , Coude FX , Bougault I , Maffrand JP , Soubrie P , Le Fur G
Ref : Neuroscience , 55 :629 , 1993
Abstract : Compounds possessing neurotrophic properties may represent a possible treatment for neurodegenerative disorders such as Alzheimer's disease. SR 57746A, 1-[2-(naphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,5,6- tetrahydropyridine hydrochloride, is a new compound with neurotrophic activity in a number of in vitro preparations. The neurotrophic effects of this compound have been evaluated in vivo using four distinct rat models of neurodegeneration: transient global ischaemia produced by a four-vessel occlusion; septohippocampal lesion produced by injection of vincristine sulphate into the medial septum; sciatic nerve crushing; and acrylamide-induced peripheral neuropathy. Rats were administered vehicle or 2.5-10 mg/kg p.o. SR 57746A, after initiation of the degenerative process, then once daily for 10 days in the first two models, 16 days in the third and 26 days in the fourth model. Median scores for ischaemia-induced neuronal damage were reduced by 30-40% by SR 57746A treatment in hippocampal CA1, CA2, and CA3 regions, and in the dorsal striatum. Twelve days after intraseptal vincristine administration, there was a marked loss of septohippocampal cholinergic neurons, as indicated by reduced choline acetyltransferase activity in both the septum and hippocampus. SR 57746A dose-dependently reversed this reduction in both areas. These results were confirmed by histoenzymological evaluation of hippocampal acetylcholinesterase content. SR 57746A also reversed the loss of hippocampal choline acetyltransferase induced by intraseptal vincristine in marmosets. Behavioral deficits in these models (exploratory behaviour in the former and short-term social memory in the latter) were also significantly reduced by SR 57746A treatment. In the sciatic crush model, sensorimotor function improved more rapidly in rats treated with 10 mg/kg SR 57746A. In this same model, SR 57746A (10 mg/kg/day) also significantly increased the length of regenerated nerve eight days after the crush, as measured using the pinch test. Finally, SR 57746A retarded the onset, reduced the amplitude and accelerated the recovery of acrylamide-induced peripheral neuropathy. Thus, SR 57746A possesses notable neurotrophic activity in a variety of neurodegenerative models in vivo, suggesting that the compound may possess therapeutic potential for the treatment of neurodegenerative diseases.
ESTHER : Fournier_1993_Neurosci_55_629
PubMedSearch : Fournier_1993_Neurosci_55_629
PubMedID: 8413926

Title : Pharmacological characterization of the aminopyridazine SR 95639A, a selective M1 muscarinic agonist - Schumacher_1989_Eur.J.Pharmacol_166_139
Author(s) : Schumacher C , Steinberg R , Kan JP , Michaud JC , Bourguignon JJ , Wermuth CG , Feltz P , Worms P , Biziere K
Ref : European Journal of Pharmacology , 166 :139 , 1989
Abstract : In order to design a selective M1 muscarinic agonist, we synthesized SR 95639A (morpholinoethylamino-3-benzocyclohepta-(5,6-c)-pyridazine, dihydrochloride), a semi-rigid analogue of the aminopyridazine antidepressant drug minaprine. SR 95639A displaced [3H]pirenzepine from its binding sites in rat hippocampal membranes with an IC50 value of 0.27 microM. It only weakly displaced [3H]N-methylscopolamine from cerebellar, cardiac and ileal membranes (10-48 microM), and, up to 100 microM, did not interact with the main other receptors of the rat brain. In rat isolated sympathetic ganglia, SR 95639A induced dose-dependent depolarizations which were antagonized by pirenzepine, and dose dependently suppressed the M current. These latter effects were also pirenzepine-sensitive. After i.p. or oral treatment in mice, SR 95639A never induced the classical cholinergic syndrome, up to lethal doses. Finally, SR 95639A (i.p. and p.o.) antagonized contralateral rotations induced by intrastriatal injection of pirenzepine, in mice. These results suggest that SR 95639A is a selective agonist at central muscarinic M1 receptors and may represent a useful tool for further characterization of the nature and function of muscarinic receptor subtypes.
ESTHER : Schumacher_1989_Eur.J.Pharmacol_166_139
PubMedSearch : Schumacher_1989_Eur.J.Pharmacol_166_139
PubMedID: 2792188

Title : Cholinomimetic activities of minaprine - Worms_1989_Naunyn.Schmiedebergs.Arch.Pharmacol_340_411
Author(s) : Worms P , Kan JP , Steinberg R , Terranova JP , Perio A , Biziere K
Ref : Naunyn Schmiedebergs Arch Pharmacol , 340 :411 , 1989
Abstract : The cholinomimetic activities of the antidepressant drug minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morpholinoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses. Minaprine and SR 95070B antagonized rotations induced by an intrastriatal injection of pirenzepine in mice, after intraperitoneal and/or oral administration. Minaprine also antagonized atropine-induced mydriasis in mice. Both minaprine and SR 95070B potentiated the tremorigenic effect of oxotremorine without inducing tremor when injected alone. Finally, minaprine and SR 95070B, after parenteral and/or oral injection, antagonized the scopolamine-induced deficit in passive avoidance learning, and enhanced short-term retention in the social memory test, in rats. The muscarinic agonists arecoline, oxotremorine and RS 86 [2-ethyl-8-methyl-2,8 diazaspiro-4,5 decan-1,3 dion hydrobromide], as well as the acetylcholine esterase inhibitors physostigmine and tacrine were active in most of these models. These results indicate that minaprine, and its metabolite SR 95070B, have cholinomimetic activities which could be, at least in part, mediated by their selective affinity for M1 muscarinic receptors. Thus minaprine could represent a potential useful drug for the treatment of senile dementias and cognitive impairments occurring in elderly people.
ESTHER : Worms_1989_Naunyn.Schmiedebergs.Arch.Pharmacol_340_411
PubMedSearch : Worms_1989_Naunyn.Schmiedebergs.Arch.Pharmacol_340_411
PubMedID: 2586634