Papers by Jean-pierre Maffrand
Thrombosis Research, 1993
High doses of aprotinin have been shown to reduce blood loss and blood transfusion requirements i... more High doses of aprotinin have been shown to reduce blood loss and blood transfusion requirements in patients undergoing open heart surgery and recent studies in animals have shown that aprotinin was able to reduce bleeding associated with rt-PA administration. Our study was designed to demonstrate an effect of aprotinin (Iniprol) on the prolongation of the bleeding time associated with the treatment with a potent analogue of ticlopidine: clopidogrel. Bleeding time was determined in rats by transection of the tip of the tail. 2 hours after a single oral administration, clopidogrel (5 mg/kg, p.o.), induced a 4-fold increase in the bleeding time. Aprotinin administered as a bolus iv injection followed by continuous infusion strongly reduced bleeding time prolongation associated with clopidogrel treatment. This effect was dose-related and reached a maximum (congruent to 50% inhibition--P < 0.001) at and above the total dose of 40 U Ph Eur/kg (80,000 KIU/kg). After administration of a total dose of 60 U Ph Eur/kg (120,000 KIU/kg), aprotinin modified neither the antiaggregating effect of clopidogrel nor its antithrombotic activity, as determined in various experimental models. For this reason, aprotinin might constitute a useful antagonist of the haemorrhagic risk associated with interventional therapy under treatment with ticlopidine or clopidogrel.
Seminars in Thrombosis and Hemostasis, 1989
Proceedings of the National Academy of Sciences, 1999
Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is a widely ... more Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is a widely used animal model for multiple sclerosis (MS) and, as in MS, clinical signs of EAE are associated with blood-brain barrier (BBB) disruption. SR 57746A, a nonpeptide drug without classical immunosuppressive properties, efficiently protected the BBB and impaired intrathecal IgG synthesis (two conventional markers of MS exacerbation) and consequently suppressed EAE clinical signs. This compound inhibited EAE-induced spinal cord mononuclear cell invasion and normalized tumor necrosis factor alpha and IFN-gamma mRNA expression within the spinal cord. These data suggested that pharmacological intervention aimed at inhibiting proinflammatory cytokine expression within the central nervous system provided protection against BBB disruption, the first clinical sign of EAE and probably the key point of acute MS attacks. This finding could lead to the development of a new class of compounds for oral therapy of MS, as a supplement to immunosuppressive agents.
Proceedings of the National Academy of Sciences, 2008
Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One o... more Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/ SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC 50 value ؍ 10 nM with FcM29, a chloroquineresistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26 -32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules.
Peptides, 1999
We have cloned the guinea pig neuropeptide Y (NPY) Y1 receptor and found it to be 92-93% identica... more We have cloned the guinea pig neuropeptide Y (NPY) Y1 receptor and found it to be 92-93% identical to other cloned mammalian Y1 receptors. Porcine NPY and peptide YY (PYY) displayed affinities of 43 pM and 48 pM, respectively. NPY2-36 and NPY3-36 had 6- and 46-fold lower affinity, respectively, than intact NPY. Functional coupling was measured by using a microphysiometer. Human NPY and PYY were equipotent in causing extracellular acidification with EC50 values of 0.59 nM and 0.69 nM, respectively, whereas NPY2-36 and NPY3-36 were about 15-fold and 500-fold less potent, respectively, than NPY. The present study shows that the cloned guinea pig Y1 receptor is very similar to its orthologues in other mammals, both with respect to sequence and pharmacology. Thus, results from previous studies on guinea pig NPY receptors might imply the existence of an additional Y1-like receptor sensitive to B1BP3226.
Neuroendocrinology, 1999
... SR-49059 in the Rat Brain: An in vitro and in vivo Autoradiographic Study Eliane Tribollet a ... more ... SR-49059 in the Rat Brain: An in vitro and in vivo Autoradiographic Study Eliane Tribollet a , Danielle Raufaste b , Jean-Pierre Maffrand b , Claudine Serradeil-Le Gal ... 31. Manning M, Sawyer WH: Discovery, development and some uses of vasopressin and oxytocin antagonists. ...
![Research paper thumbnail of Autoradiographic localization of vasopressin V1a receptors in the rat kidney using [3H]-SR 49059](https://attachments.academia-assets.com/42402368/thumbnails/1.jpg)
Kidney International, 1996
Localization and characterization of binding sites of the selective non-peptide vasopressin recep... more Localization and characterization of binding sites of the selective non-peptide vasopressin receptor V1a ligand, [3H]-SR 49059, were investigated in the adult rat kidney by quantitative autoradiography using a fast-detecting radioluminographic phosphor-imaging plate system. [3H]-SR 49059, like the other V1a ligands used, showed a total absence of binding in the papilla, discrete and sparse labeling in the cortex and maximal binding in the outer part of the inner medulla. This labeling seemed to be mainly associated with medullary interstitial cells and vascular elements of the vasa recta. Conversely, [3H]-AVP intensely labeled the V2-enriched medulla-papillary portion of the kidney and, to a lesser extent, the cortical structures. [3H]-SR 49059 binding, quantified in the outer part of the inner medulla in rat kidney sections, was time-dependent, reversible, saturable and a single class of high affinity binding sites (Kd = 1.48 +/- 0.16 nM) was identified. The relative potencies of the reference peptide and non-peptide compounds to inhibit [3H]-SR 49059 binding confirm the V1a nature of the site and the stereospecificity of this binding. Thus, [3H]-SR 49059 allows the mapping and characterization of the V1a receptor population present in the rat kidney. The stability and the highly selective affinity of this non-peptide ligand for rat and human V1a receptors make it a suitable probe for the localization of V1a receptors in organs expressing heterogeneous populations of receptors.
![Research paper thumbnail of Binding properties of a selective tritiated vasopressin V2 receptor antagonist, [3H]-SR 121463](https://attachments.academia-assets.com/42402367/thumbnails/1.jpg)
Kidney International, 2000
[3H]-SR 121463 is the first radiolabeled selective nonpeptide vasopressin V2 receptor antagonist ... more [3H]-SR 121463 is the first radiolabeled selective nonpeptide vasopressin V2 receptor antagonist ligand that has been reported to date. In the present work, we studied the binding properties of [3H]-SR 121463 for renal V2 receptors from animal and human origins. Binding studies were performed with [3H]-SR 121463 in Chinese hamster ovary (CHO) cells transfected with the human V2 receptor and in various kidney preparations expressing the native V2 receptors (rat, rabbit, dog, pig, monkey, and human). Autoradiographies were performed in rat and human kidney sections. [3H]-SR 121463 binding to CHO cells stably transfected with the cloned human renal V2 receptor was specific, highly stable, time dependent, saturable, and reversible. A single population of high-affinity binding sites was identified (Kd = 0.94 +/- 0.34 nmol/L, Bmax = 9876 +/- 317 fmol/mg protein). Of note, [3H]-SR 121463 revealed a higher number (about 40%) of V2 sites than [3H]-AVP in the same preparation. Displacement of [3H]-SR 121463 binding by reference peptide and nonpeptide vasopressin/oxytocin compounds exhibited a typical AVP V2 profile. [3H]-SR 121463 also displayed a high affinity for native V2 receptors in several kidney preparations from rat, pig, dog, rabbit, bovine, monkey, and human. The autoradiographic experiments using rat and human kidney sections showed intense labeling in the medullopapillary region and lower intensity in the cortex, consistent with a main localization of V2 receptors on collecting tubules. [3H]-SR 121463 is a useful ligand for the specific labeling of animal and human V2 receptors and could be a suitable probe for the search and in situ localization of V2 sites.
Journal of Ocular Pharmacology and Therapeutics, 2000
The activity on intraocular pressure (IOP) of SR121463, a selective non-peptide arginin-vasopress... more The activity on intraocular pressure (IOP) of SR121463, a selective non-peptide arginin-vasopressin (AVP) V2 receptor antagonist, was investigated in a rabbit model of ocular hypertension. We first demonstrated that, in vitro, SR121463 displayed high competitive affinity for rabbit vasopressin V2 receptors (Ki = 2.1 +/- 1.2 nM). In vivo, SR121463 was instilled once (at concentrations ranging from 0.1 to 3%), or for 10 days (20 instillations) at 1% concentration, in the eye of ocular hypertensive rabbits (intraocular injection of 0.14 mg alpha-chymotrypsin). SR121463 also was instilled at 1% in the normotensive eye or intravenously injected (100 microg/kg) to ocular hypertensive rabbits. SR121463 was compared to timolol 0.5% or to clonidine 0.25%. Additionally, local and systemic safety aspects were examined. Results showed that SR121463 was locally well-tolerated and had no anesthetic effect. A significant decrease in IOP of the hypertensive eye was observed for concentrations of SR121463 > or =1%. This decrease was comparable to that obtained with reference compounds. A similar activity was found after intravenous administration. No tachyphylaxis was observed after 10 days, and no contralateral or systemic effect was noted. Also, when applied on the normotensive eye or when intravenously injected, SR121463 had no effect on the normotensive eye. These results on IOP and the good local and systemic safety profile, suggest that a potent vasopressin V2 receptor antagonist, SR121463, could be of value for the treatment of glaucoma, through a mechanism of action that remains to be elucidated.
Journal of Medicinal Chemistry, 1997
The platelet fibrinogen receptor GpIIb-IIIa is currently considered a target of choice for drugs ... more The platelet fibrinogen receptor GpIIb-IIIa is currently considered a target of choice for drugs used in the prevention and treatment of thrombosis. Ethyl 3-[N-[4-[4-[amino[(ethoxycarbonyl)-imino] methyl]phenyl]-1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl] piperid-4-yl] amino]propionate (6, SR 121787) is a new antiaggregating agent which generates in vivo the corresponding diacid 19d (SR 121566), non-peptide GpIIb-IIIa antagonist. In vitro, 19d inhibited ADP-induced aggregation of human and baboon platelets (IC50 = 46 +/- 11 and 54 +/- 6 nM, respectively), and on human platelets, 19d antagonized the binding of 125I-labeled fibrinogen (IC50 = 19.2 +/- 6.2 nM). Ex vivo, 8 h after an i.v. administration of 19d (100 micrograms/kg, i.v.) to baboons, ADP-induced aggregation was strongly inhibited (more than 90%). At 8 h, the ED50 value was 24 +/- 3.3 micrograms/kg), and even 24 h after the administration of a single dose of 100 micrograms/kg of 19d, platelet aggregation was still significantly inhibited (50 +/- 6% inhibition, P < 0.05). In the same species, the oral administration of 500 micrograms/kg of 6 produced a nearly complete inhibition of aggregation for up to 8 h (ED50 at 8 h was 193 +/- 20 micrograms/kg). After an oral dose of 2 mg/kg of 6, an antiaggregating effect was still observed at 24 h (44 +/- 12% inhibition, P < 0.05). 6 was well tolerated in animals, showing that, on the basis of these studies, it is a suitable candidate for development as an orally active antithrombotic agent.
Journal of Cellular Physiology, 1989
The binding, internalization, and metabolism of [3H]-heparin by human umbilical vein endothelial ... more The binding, internalization, and metabolism of [3H]-heparin by human umbilical vein endothelial cells (HUVEC) and human umbilical arterial smooth muscle cells (HUASMC) have been characterized using size-exclusion HPLC. Incubation of HUVEC with [3H]-heparin demonstrated selective binding of high-molecular-weight (MW) components (MW = 21 kd), which was followed by rapid, temperature-dependent internalization. Over the next 3 hours, this internalized [3H]-heparin was degraded to low-MW fragments (MW = 0.9 kd). Primary cultures of HUASMC selectively bound extremely high-MW components (MW = 40 kd) and also smaller components whose MW (0.9 kd) corresponded to that of the heparin metabolite(s) formed by HUVEC. Subcultured HUASMC bound only the 40-kd components. Internalization of heparin by smooth muscle cells (SMC) was significantly slower than that determined for HUVEC, and even after 4 hours there was no evidence of the heparin being metabolized. However, when incubating primary rabbit aortic SMC with purified low-MW heparin fragment(s) produced in culture by HUVEC, a significantly lower proliferative response of these cells (IC50 = 18.4 micrograms/ml) was obtained. Virtually no effect was observed with subcultured SMC in the range of the tested concentrations (0-20 micrograms/ml). These fragments were 10- to 15-fold more effective in inhibiting primary SMC growth than was standard heparin. Furthermore, heparin fractions in the same range of molecular weights, purified either after nitrous acid or heparinase depolymerization of standard heparin, showed no activity on primary SMC growth, thus indicating a high degree of selectivity of the heparin metabolite(s) produced by HUVEC in culture.
Fundamental and Clinical Pharmacology, 2001
FEBS Letters, 1997
Characterization and localization of leptin binding sites were investigated in rat kidneys using ... more Characterization and localization of leptin binding sites were investigated in rat kidneys using [125I]leptin as a ligand. [125I]Leptin specific binding was found in high amounts in rat renomedullary membranes. This binding was specific, saturable, time-dependent (K(obs) = 0.055 +/- 0.008 min(-1)) and the dissociation of receptor-bound ligand was slowly reversible (K(-1) = 0.048 +/- 0.013 min(-1)). From saturation experiments, a single class of high-affinity binding sites for leptin was identified with an apparent K(d) of 0.57 +/- 0.14 nM and a B(max) of 45 +/- 10 fmol/mg protein. [125I]Leptin binding was inhibited in a dose-dependent manner by cold leptin and was highly selective since not displaceable by a number of other hormones or peptides. Autoradiographic experiments performed on adult rat kidney sections showed the intense presence of [125I]leptin receptors only in specific areas of the renal inner medulla and also consistent labeling associated with vascular structures in the corticomedullary region. The study of the postnatal developmental expression of leptin receptors in the kidney showed very low expression during the early postnatal period (8-21 days). Full expression of leptin sites was achieved at about 30 days and remained stable throughout adulthood (60 days and upwards). Moreover, in vivo administration of leptin (0.5 mg/kg i.p.) induced a significant and rapid diuretic effect in normally hydrated conscious rats. Thus, these data constitute the first characterization and mapping of [125I]leptin specific binding sites in the rat kidney and raise the possibility of a renal control by leptin.
FEBS Letters, 1995
An orally-active antagonist of neuropeptide Y (NPY) Y1 receptors, SR 120819A, has been characteri... more An orally-active antagonist of neuropeptide Y (NPY) Y1 receptors, SR 120819A, has been characterized. This compound displays highly selective and competitive affinity for rat, guinea-pig and human (Ki = 15 nM) NPY Y1 receptors. In vitro, SR 120819A blocks the inhibitory effect of NPY on adenylyl cyclase activity in human SK-N-MC cells and that of the selective Y1 agonist, [Leu31,Pro34]NPY, on rabbit vas deferens contraction (pA2 = 7.20 +/- 0.07). In vivo, by intravenous route, this compound acts as an antagonist in anesthetized guinea-pigs and, notably, after oral administration, SR 120819A counteracts the pressor response of [Leu31,Pro34]NPY (5 micrograms/kg i.v.) with a long duration of action (> 4 h at 5 mg/kg p.o.). Thus, SR 120819A is the first orally-effective NPY Y1 receptor antagonist yet described. It could be a useful tool for exploring the role of NPY and the therapeutic relevance of an antagonist at NPY Y1 receptors.
FEBS Letters, 2000
In order to characterize neuropeptide Y (NPY) receptors present in human adipocytes, we used sele... more In order to characterize neuropeptide Y (NPY) receptors present in human adipocytes, we used selective ligands together with specific molecular probes able to recognize the different NPY receptor subtypes. RT-PCR experiments revealed the presence of Y(1) receptor transcripts with Y(4) and Y(5) and absence of Y(2) signals. Binding studies, using selective radioiodinated ligands, detected a high number (B(max)=497+/-124 fmol/mg protein) of a high affinity binding site only with [(125)I]peptide YY (PYY) and [(125)I](Leu(31), Pro(34))PYY. These sites exhibited a typical Y(1) profile as indicated by the rank order of affinity of NPY analogs and the high affinity of two selective NPY receptor antagonists, SR120819A and BIBP3226. In [(35)S]GTPgammaS binding experiments, PYY activation was totally inhibited by SR120819A and BIBP3226. Both compounds antagonized, with similar efficiency, the antilipolytic effect exerted by NPY in isolated adipocytes. Finally, PYY and Y(1) ligands enhanced adipocyte leptin secretion, an effect totally prevented by SR120819A. Thus, highly expressed in human adipocytes, the Y(1) receptor sustains the strong antilipolytic effect of NPY and exerts a positive action on leptin secretion.
FEBS Letters, 1998
Stimulation of neurotensin (NT) type 1 receptors (NT1-R) in transfected CHO cells is followed by ... more Stimulation of neurotensin (NT) type 1 receptors (NT1-R) in transfected CHO cells is followed by the activation of mitogen-activated protein kinases and the expression of the early response gene krox24. By making point mutations and internal deletions in the krox24 promoter, we show that proximal serum responsive elements (SRE) are involved in transcriptional activation by NT. In addition, we show that the related early response gene c-fos and the Ets protein Elk-1 are also induced by NT. The involvement of NT1-R in NT-mediated activation of krox24, c-fos and Elk-1 was demonstrated by the preventing effect of the specific antagonists SR 48692 and SR 142948. Finally, we show that the activation of krox24 and Elk-1 on the one hand, and that of c-fos on the other hand, result from independent transduction pathways since the former are pertussis toxin-sensitive whereas the latter is insensitive to pertussis toxin.
European Journal of Pharmacology, 2002
We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid ... more We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid receptor agonists (+)-WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) and CP 55,940 ((-)-cis-3[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), as prevented by the selective cannabinoid CB(1)-receptor antagonist SR141716 ((N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)) in rats after systemic or central drug administration. Oral SR141716 showed comparable potency (ID(50) range 1.0-3.9 mg/kg) in antagonizing gastric emptying and gastrointestinal transit delay by (+)-WIN 55,212-2 or CP 55,940. Gastric emptying and gastrointestinal transit delay after intracerebroventricular (i.c.v.) (+)-WIN 55,212-2 was prevented by oral or i.c.v. SR141716, but i.c.v. SR141716 did not significantly reduce the effect of i.p. (+)-WIN 55,212-2. Pertussis toxin prevented the delaying action of i.c.v. (+)-WIN 55,212-2 on both gastric emptying and gastrointestinal transit, but had no effect on (+)-WIN 55,212-2 i.p. These findings are consistent with a primary role of peripheral cannabinoid CB(1) receptor mechanisms in gastrointestinal transit delay by specific agonists.
European Journal of Pharmacology, 1994
Neurotensin has been suggested to be involved in neurological and mental disorders associated wit... more Neurotensin has been suggested to be involved in neurological and mental disorders associated with altered dopaminergic transmission. The lack of a potent neurotensin receptor antagonist had prevented us from studying the real physiological implication of this peptide in brain function. We thus recently developed such a non-peptide neurotensin receptor antagonist, SR 48692,
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Papers by Jean-pierre Maffrand