共查询到20条相似文献,搜索用时 31 毫秒
1.
Hervé Minoux Nicolas Moitessier Yves Chapleur Bernard Maigret 《Letters in Peptide Science》1997,4(4-6):463-466
The aim of this work was to elucidate, usingmolecular modeling, structural and electrostaticcommon parameters of several selective fibrinogenreceptor antagonists. From this theoretical pattern,we are currently designing and synthesizing originalnon-peptidic and selective carbohydrate-basedantagonists of the fibrinogen receptor. 相似文献
2.
To determine which subtype of α1-adrenergic receptors plays a role in the regulation of blood pressure, with α1A-adrenergic receptor-mediated vasoconstriction in perfused hindlimb as a control, we compared the inhibitory effects of various α1-adrenergic receptor selective antagonists on the vasopressure responses to phenylephrine between the mean arterial pressure and hindlimb perfusion pressure in anesthetized rats. In Normotensive Wistar rats, the results showed that the inhibitory effects (dose ratios of ED50, Dr) of α1-adrenoceptor selective antagonist (prazosin, Dr 13.5 ± 3.6 vs.15.1 ± 4.3, n = 11), α1A-adrenoceptor selective antagonist (5-methyl-urapidil, Dr 2.4 ± 0.9 vs. 3.7 ± 2.3, n = 12; RS-17053, Dr 3.2 ± 1.6 vs. 4.4 ± 3.3, n = 12) and α1D-adrenoceptor selective antagonist (BMY7378, Dr 1.9 ± 0.9 vs. 2.2 ± 0.8, n = 8) on phenylephrine-induced increases of perfusion pressure in the autoperfused femoral beds were the same as that in the mean arterial blood pressure in normotensive Wistar rats. The inhibitory effects of antagonists (RS-17053, Dr 3.4 ± 0.6 vs. 4.3 ± 0.9, n = 5; BMY7378, Dr 1.7±0.5 vs. 1.7 ± 0.5, n = 8) in spontaneous hypertensive rats were similar with the Wistar rats. These results suggest that the mean arterial pressure induced by phenylephrine was mainly mediated by α1A-adrenergic receptor in both the anesthetized Wistar rats and spontaneous hypertensive rats. 相似文献
3.
Nicolas Moitessier Hervé Minoux Bernard Maigret Françoise Chrétien Yves Chapleu 《International journal of peptide research and therapeutics》1998,5(2-3):75-78
Summary Modeling studies of several known antagonists of the fibrinogen receptor have provided a theoretical pattern of the essential
characteristics for high affinity and selectivity toward this receptor. Potentially active and selective antagonists of the
fibrinogen receptor were thus designed by computational comparison of their aqueous conformations with that of known selective
antagonists, and synthesized by grafting suitable functional groups on a D-xylose scaffold. 相似文献
4.
Nicolas Moitessier Hervé Minoux Bernard Maigret Françoise Chrétien Yves Chapleu 《Letters in Peptide Science》1998,5(2-3):75-78
Modeling studies of several known antagonists of the fibrinogen receptor have provided a theoretical pattern of the essential characteristics for high affinity and selectivity toward this receptor. Potentially active and selective antagonists of the fibrinogen receptor were thus designed by computational comparison of their aqueous conformations with that of known selective antagonists, and synthesized by grafting suitable functional groups on a D-xylose scaffold. 相似文献
5.
Nielsen DM 《Life sciences》2006,78(9):909-919
Corticotropin-releasing factor (CRF) is a neuropeptide that plays a primary role in the neuroendocrine, autonomic, and behavioral responses to stressors. Numerous reports suggest that alterations in CRF function contribute to the pathogenesis of depression. Recently, selective nonpeptide CRF type 1 (CRF1) receptor antagonists have been discovered and several of these CRF1 receptor antagonists have demonstrated antidepressant-like efficacy in animals. The CRF1 receptor antagonists appear to be unique, as they exhibit antidepressant-like activity principally in animal models that are hyperresponsive to stress or under experimental conditions that alter endogenous stress-hormone activity. A nonpeptide CRF1 receptor antagonist has also been shown to reduce symptoms of major depression in an open-label clinical trial. Accumulating evidence supports a role for nonpeptide CRF1 receptor antagonists among the future pharmacotherapies for the treatment of depression. 相似文献
6.
Urbano M Guerrero M Zhao J Velaparthi S Schaeffer MT Brown S Rosen H Roberts E 《Bioorganic & medicinal chemistry letters》2011,21(18):5470-5474
Recent evidence suggests an innovative application of chemical modulators targeting the S1P(4) receptor as novel mechanism-based drugs for the treatment of influenza virus infection. Modulation of the S1P(4) receptor may also represent an alternative therapeutic approach for clinical conditions where reactive thrombocytosis is an undesired effect or increased megakaryopoiesis is required. With the exception of our recent research program disclosure, we are not aware of any selective S1P(4) antagonists reported in the literature to date. Herein, we describe complementary structure-activity relationships (SAR) of the high-throughput screening (HTS)-derived hit 5-(2,5-dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide and its 2,5-dimethylphenyl analog. Systematic structural modifications of the furan ring showed that both steric and electronic factors in this region have a significant impact on the potency. The furan moiety was successfully replaced with a thiophene or phenyl ring maintaining potency in the low nanomolar range and high selectivity against the other S1P receptor subtypes. By expanding the molecular diversity within the hit-derived class, our SAR study provides innovative small molecule potent and selective S1P(4) antagonists suitable for in vivo pharmacological validation of the target receptor. 相似文献
7.
An update on non-peptide angiotensin receptor antagonists and related RAAS modulators 总被引:1,自引:0,他引:1
The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists. 相似文献
8.
9.
Stock N Volkots D Stebbins K Broadhead A Stearns B Roppe J Parr T Baccei C Bain G Chapman C Correa L Darlington J King C Lee C Lorrain DS Prodanovich P Santini A Evans JF Hutchinson JH Prasit P 《Bioorganic & medicinal chemistry letters》2011,21(3):1036-1040
Compound 21 (AM432) was identified as a potent and selective antagonist of the DP2 receptor (CRTH2). Modification of a bi-aryl core identified a series of tri-aryl antagonists of which compound 21 proved a viable clinical candidate. AM432 shows excellent potency in a human whole blood eosinophil shape change assay with prolonged incubation, a comparatively long off-rate from the DP2 receptor, excellent pharmacokinetics in dog and in vivo activity in two mouse models of inflammatory disease after oral dosing. 相似文献
10.
Harro J 《Amino acids》2006,31(3):215-230
Summary. Short CCK peptides elicit panic attacks in humans and anxiogenic-like effects in some animal models, but CCK receptor antagonists
have not been found clinically effective. Yet CCK overactivity appears to be involved in submissive behaviour, and CCKB receptor expression and binding are increased in suicide victims and animal models of anxiety. Preliminary data suggest that
involvement of CCK and its receptor subtypes in anxiety can be better described when focusing on distinct endophenotypes,
and considering environmental contingencies and confounds originating from interactions with dopamin-, opioid- and glutamatergic
neurotransmission. In contrast, NPY is an anti-anxiety peptide with robust effects in various animal models when administrated
into several brain regions. Studies with non-peptide antagonists selective for receptor subtypes have revealed the role of
endogenous NPY in active coping. At least Y1, Y2 and Y5 receptors in various brain regions are involved, with the strongest evidence for contribution of Y1. 相似文献
11.
Guerrero M Urbano M Velaparthi S Zhao J Schaeffer MT Brown S Rosen H Roberts E 《Bioorganic & medicinal chemistry letters》2011,21(12):3632-3636
Selective S1P4 receptor antagonists could be novel therapeutic agents for the treatment of influenza infection in addition to serving as a useful tool for understanding S1P4 receptor biological functions. 5-(2,5-Dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide was identified from screening the Molecular Libraries-Small Molecule Repository (MLSMR) collection and selected as a promising S1P4 antagonist hit with moderate in vitro potency and high selectivity against the other family receptor subtypes (S1P1-3,5). Rational chemical modifications of the hit allowed the disclosure of the first reported highly selective S1P4 antagonists with low nanomolar activity and adequate physicochemical properties suitable for further lead-optimization studies. 相似文献
12.
Jain KS Bariwal JB Kathiravan MK Phoujdar MS Sahne RS Chauhan BS Shah AK Yadav MR 《Bioorganic & medicinal chemistry》2008,16(9):4759-4800
Hypertension is one of the most serious health problems of the modern world with a continuous rise in the number of patients. Selective α1-adrenoreceptor antagonists though have many advantages and uses in the management of arterial hypertension, their lack of specificity at the level of α1-adr subtypes leads to multiple side effects. Existence of multiple α1-adr subtypes holds great promise for the discovery and development of more specific and selective drug molecules, targeting only one α1-adr subtype at a time and thus relative freedom from side effects. Herein, the research done on the discovery and evaluation of a variety of chemically diverse structures as selective antagonists of α1-adr and α1-adr subtypes in recent years has been reviewed. 相似文献
13.
Matasi JJ Brumfield S Tulshian D Czarnecki M Greenlee W Garlisi CG Qiu H Devito K Chen SC Sun Y Bertorelli R Geiss W Le VD Martin GS Vellekoop SA Haber J Allard ML 《Bioorganic & medicinal chemistry letters》2011,21(12):3805-3808
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X7 receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X7 receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models. 相似文献
14.
Dian Zhang Bingxiang Yuan Xiuling Deng Guangde Yang Langchong He Youyi Zhang Qide Han 《中国科学:生命科学英文版》2004,47(4):376-381
To improve selectivity and specificity of cell membrane chromatography (CMC), the chromatography affinities of nine ligands of α1-adrenergic receptor(AR)to α1D-AR subtype were investigated. The human embryonic kidney (HEK) 293 cells expressed by cDNA of α1D-AR subtypes were cultured and cell membrane stationary phase (CMSP) was prepared. Then the interactions between ligands and α1D-AR in CMSP were investigated using CMC. The affinity rank order to α1D-AR subtype obtained from CMC for the nine α1-adrenoceceptor ligands is: prazosin, BMY7378, phentolamine, oxymetazoline, 5-methylurapidil, norepinephrine, phenyle-phrine, methoxamine, RS-17053. The affinity rank order is similar and correlates well with that obtained from others’ radioligand binding assays (RBA). CMSP prepared by transfected HEK293 cells with α1D-adrenoceptor cDNA and CMC method could be used to evaluate affinities of drug-receptor and drug-receptor subtypes and to screen drugs selective to α1D-AR. 相似文献
15.
Summary. It has been proposed that glutamatergic transmission, in particular NMDA receptor function, might be altered in schizophrenia.
This hypothesis is mainly based on the observation that uncompetitive NMDA receptor antagonists, e.g. phencyclidine, evoke
psychotic symptoms in healthy subjects, whereas agonists interacting at the glycine site of the NMDA receptor complex, e.g.
glycine or D-serine, administered jointly with typical neuroleptics, can alleviate schizophrenic symptoms. The function of
NMDA receptors may be modulated by group I mGluRs (mGluR1 and mGluR5), which have also been shown to be altered in schizophrenia.
In rodents, mGluR5 antagonists, but not mGluR1 ones, potentiate the locomotor activity and the deficit of prepulse inhibition
(PPI) induced by uncompetitive NMDA receptor antagonists. These antagonists (of either type) administered alone are not active
in the above tests. Hence, antagonists of mGluR1 and mGluR5 may evoke different effects on the NMDA receptor antagonists-induced
behavior and, possibly, on schizophrenic symptoms. 相似文献
16.
Doleviczényi Z Vizi ES Gacsályi I Pallagi K Volk B Hársing LG Halmos G Lendvai B Zelles T 《Neurochemical research》2008,33(11):2364-2372
In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory
system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve
dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume
superfusion techniques we tested 5-HT6 and 5-HT7 receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic
conditions using currently available and new 5-HT6 and 5-HT7 antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT7 antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT6 receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type
of receptor. Moreover, the mixed 5-HT6/7 antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of
an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement
of an indirect neural mechanism through an inhibitory system. In the presence of the GABAA receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation
of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic
inhibitory tone on dopaminergic nerve endings. The mixed 5-HT7/D4 receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the
selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from
the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals
in the cochlea may have a role in the treatment of sensorineural hearing loss. 相似文献
17.
Napier S Wishart G Arbuckle W Baker J Barn D Bingham M Brown A Byford A Claxton C Craighead M Buchanan K Fielding L Gibson L Goodwin R Goutcher S Irving N MacSweeney C Milne R Mort C Presland J Sloan H Thomson F Turnbull Z Young T 《Bioorganic & medicinal chemistry letters》2011,21(10):3163-3167
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V1A receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V1A antagonists. 相似文献
18.
Mary Chebib Navnath Gavande Kit Yee Wong Anna Park Isabella Premoli Kenneth N. Mewett Robin D. Allan Rujee K. Duke Graham A. R. Johnston Jane R. Hanrahan 《Neurochemical research》2009,34(10):1704-1711
GABAC receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective
agents for this class of receptors. Guanidino analogs related to glycine, β-alanine and taurine were evaluated at human ρ1GABAC receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining
were inactive. (S)-2-Guanidinopropionic acid (IC50 = 2.2 μM) and guanidinoacetic acid (IC50 = 5.4 μM; K
B = 7.75 μM [pK
B = 5.11 ± 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the β-alanine and GABA
guanidino analogs showed reduced activity, indicating the distance between the carboxyl carbon and terminal nitrogen of the
guanidino group is critical for activity. Substituting the C2-position of guanidinoacetic acid with various alkyl groups reduced
activity indicating that steric effects may impact on activity. The results of this study contribute to the structure–activity-relationship
profile required in developing novel therapeutic agents. 相似文献
19.
Cowley PM Baker J Buchanan KI Carlyle I Clark JK Clarkson TR Deehan M Edwards D Kiyoi Y Martin I Osbourn D Walker G Ward N Wishart G 《Bioorganic & medicinal chemistry letters》2011,21(7):2034-2039
The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB1 receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB1 antagonist with high predicted human oral bioavailability. 相似文献
20.
Butera D Skielka K McLane MA Paquette-Straub C Ducancel F da Silva AM 《Protein expression and purification》2003,31(2):286-291
Integrins are transmembrane heterodimeric glycoproteins responsible for cellular communication; therefore, they play an essential role in many physiological events. Viper snake venoms contain integrin antagonists called disintegrins which bind and inhibit integrin function. They present a loop containing an RGD motif responsible for integrin binding. The engineering of disintegrins fused to a reporter enzyme will be an interesting approach to build integrin markers. Even more, the disintegrin scaffold could be used to present other protein binding motifs. In this work, we have obtained alkaline phosphatase (APv) tagged eristostatin (Er) by cloning and expressing eristostatin DNA into the pLIP6-GN vector. Eristostatin, a 49 residue disintegrin, binds selectively to alphaIIbbeta3 integrin, inhibiting its binding to fibrinogen. The resulting fusion protein Er/APv was identified by SDS-PAGE and by Western blotting using both anti-Er and anti-AP antibodies. This fusion protein showed enzymatic AP activity similar to that of wild APv and its potential use for an alphaIIbbeta3 integrin assay was tested in a one-step dot blot using immobilized cells incubated with the marker and developed by AP substrate. Er/APv showed selectivity towards platelets and alphaIIbbeta3 integrin transfected cells and reacted with the same region as unlabeled Er, as analyzed in competition assays. Our data present a novel tool, Er/APv, with potential use as molecular marker in processes where the alphaIIbbeta3 integrin is involved. 相似文献