Glutamate receptor antagonists attenuate experimental catalepsy in rats

A long-term akinesia induced by haloperidol used as an experimental model of catalepsy helped to reveal that a dicationic derivatives adamantane (IEM-1754) and phenylcyclohexyl (IEM-1925) exerted different degrees of inhibition of the haloperidol effect: the IEM-1754 proved to be not inferior to the most effective NMDA antagonist MK-801. A relatively low potency of the IEM-1925 may be due to its obvious equal effects both on the NMDA and the AMPA receptor channels. A good correlation between the anticataleptic effects of the glutamate antagonists and the NMDA receptor blocking activity, were found. The AMPA receptor blockade might negatively affect the anticataleptic potency of the drugs under study.     

Bradykinin antagonists: new opportunities

The pro-inflammatory, pain producing, and cardiovascular effects of bradykinin B2 receptor activation are well characterized. Bradykinin B1 receptors also produce inflammation and pain. Therefore, antagonists are expected to be anti-inflammatory/analgesic drugs. Other exploitable clinical opportunities may exist. The newly discovered non-peptide B2 receptor antagonists and the equivalent B1 receptor pharmacological agents, which are in the pipeline, are suitable preclinical tools to properly evaluate potential utilities.     

Bradykinin antagonists: Development and applications

Bradykinin (BK) is involved in regulation of every major physiological system and is an initiator or mediator of many pathophysiological conditions. Rapid progress in understanding these aspects of BK biology has come since the discovery of BK antagonists. This article reviews principal points in the history of the kallikrein–kinin field and of kinin biology. The chemistry and development of antagonists for B1 and B2 kinin receptors is discussed. Uses of the antagonists in biomedical research and potential clinical applications are presented. © 1994 John Wiley & Sons, Inc.     

Bradykinin antagonists: discovery and development

Practical bradykinin antagonists were discovered in 1984 by Vavrek and Stewart and reported in "Peptides." At that time there was already much evidence for involvement of bradykinin in inflammation and pain, so the specific, competitive antagonists were widely accepted and applied. The key to conversion of bradykinin into an antagonist was replacement of the proline residue at position 7 with a D-aromatic amino acid. Other modifications converted the initial weak antagonists into modern peptides which are totally resistant to all degrading enzymes, are orally available, and have been used in clinical trials. Non-peptide bradykinin antagonists have also been developed.     

Bradykinin B1 receptor antagonists: an alpha-hydroxy amide with an improved metabolism profile

A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.     

Discovery of dihydroquinoxalinone acetamides containing bicyclic amines as potent Bradykinin B1 receptor antagonists

Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC(50)s<0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure-activity relationship (SAR) for these analogs.     

Bradykinin antagonists modified with dipeptide mimetic beta-turn inducers

Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic beta-turn inducers.     

Nonpeptide endothelin receptor antagonists attenuate the pressor effect of diaspirin-crosslinked hemoglobin in rat.

Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is thought to participate in the hemodynamic effects elicited by drugs that block the biosynthesis and release of endothelium-derived nitric oxide (NO), such as NO synthase inhibitors. Using the nonpeptide endothelin receptor antagonists bosentan and LU-135252, we tested the hypothesis that endothelins contribute to the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, whose pressor activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME), ET-1, and noradrenaline (NA) were used as reference drugs. Bosentan markedly reduced the pressor effects elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-135252 attenuated the pressor effect elicited by DCLHb and ET-1, but not that produced by L-NAME or NA. The decreases in heart rate associated with the pressor effect of DCLHb and L-NAME were reduced by LU-135252, whereas only those elicited by DCLHb were attenuated by bosentan. In contrast with bosentan, LU-135252 caused a decrease in the baseline blood pressure and heart rate. These results suggest that endothelins may participate in the pressor activity of DCLHb. They suggest also that nonpeptide endothelin receptor antagonists such as bosentan or LU-135252 may be useful to counteract endothelin-mediated undesirable hemodynamic effects of drugs that inhibit the activity of the NO system.     

Bradykinin antagonists with dehydrophenylalanine analogues at position 5

Continuing the studies on structural requirements of bradykinin antagonists, it has been found that analogues with dehydrophenylalanine (ΔPhe) or its ring‒substituted analogues (ΔPhe(X)) at position 5 act as antagonists on guinea pig pulmonary artery, and on guinea pig ileum. Because both organs are considered to be bradykinin B₂receptor tissues, the analogues with ΔPhe or ΔPhe(X) at position 5, but without any replacement at position 7, seem to represent a new structural type of B₂receptor antagonist. All the analogues investigated act as partial antagonists; they inhibit the bradykinin‒induced contraction at low concentrations and act as agonists at higher concentrations. Ring substitutions by methyl groups or iodine reduce both the agonistic and antagonistic activity. Only substitution by fluorine gives a high potency. Incorporation of ΔPhe into different representative antagonists with key modifications at position 7 does not enhance the antagonist activity of the basic structures, with one exception. Only the combination of ΔPhe at position 5 with D Phe at position 7 increases the antagonistic potency on guinea pig ileum by about one order of magnitude. Radio‒ligand binding studies indicate the importance of position 5 for the discrimination of B₂receptor subtypes. The binding affinity to the low‒affinity binding site (K_L) was not significantly changed by replacement of Phe by ΔPhe. In contrast, ring‒methylation of ΔPhe results in clearly reduced binding to K_L. The affinity to the high‒affinity binding site (K_H) was almost unchanged by the replacement of Phe in position 5 by ΔPhe, whereas the analogue with 2‒methyl‒dehydrophenylalanine completely failed to detect the K_H‒site. The peptides were synthesized on the Wang‒resin according to the Fmoc/Bu^tstrategy using Mtr protection for the side chain of Arg. The dehydrophenylalanine analogues were prepared by a strategy involving PyBop couplings of the dipeptide unit Fmoc‒Gly‒ΔPhe(X)‒OH to resin‒bound fragments. © 1998 European Peptide Society and John Wiley & Sons, Ltd.     

Muscarinic antagonists attenuate dizocilpine-induced hypermotility in mice.

Pretreatment of mice with the muscarinic receptor antagonists scopolamine and atropine attenuated the hypermotility (but not the depression of rearing) induced by a low dose of dizocilpine maleate [(+)-MK-801; 0.1 mg/kg, i.p.], a non-competitive NMDA antagonist. In contrast, the muscarinic blockers failed to affect hypermotility induced by equieffective doses of phencyclidine (1 mg/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). These results suggest differences between the mechanism of behavioral activation produced by dizocilpine and phencyclidine, and demonstrate the potential of muscarinic blockade for diminishing the behavioral toxicity of NMDA antagonists.     

Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds

Glioblastoma (GB), the most aggressive brain tumour, and mantle cell lymphoma (MCL), a rare but very aggressive type of lymphoma, are highly resistant to chemotherapy. GB and MCL chemotherapy gives very modest results, the vast majority of patients experience recurrent disease. To find out the new treatment modality for drug-resistant GB and MCL cells, combining of bradykinin (BK) antagonists with conventional temozolomide (TMZ) treatment, and screening of thiazolidinones derivatives were the main objectives of this work. As it was revealed here, BKM-570 was the lead compound among BK antagonists under investigation (IC₅₀ was 3.3 μM) in human GB cells. It strongly suppressed extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation. BK antagonists did not decrease the viability of MCL cells, thus showing the cell-specific mode, while thiazolidinone derivatives, a novel group of promising anti-tumour compounds inhibited proliferation of MCL cells: IC₅₀ of ID 4526 and ID 4527 compounds were 0.27 μM and 0.16 μM, correspondingly. However, single agents are often not effective in clinic due to activation of collateral pathways in tumour cells. We demonstrated a strong synergistic effect after combinatorial treatment by BKM-570 together with TMZ that drastically increased cytotoxic action of this drug in rat and human glioma cells. Small proportion of cells was still viable after such treatment that could be explained by presence of TMZ-resistant cells in the population.It is possible to expect that the combined therapy aimed simultaneously at different elements of tumourigenesis will be more effective with lower drug concentrations than the first-line drug temozolomide used alone in clinics.     

Bradykinin B1 antagonists: biphenyl SAR studies in the cyclopropanecarboxamide series

SAR study of the biphenyl region of cyclopropanecarboxamide derived bradykinin B(1) antagonists was examined. Incorporation of a pyridine in place of the proximal phenyl ring and chlorination of the distal phenyl ring proved to be well tolerated and provided compounds with improved pharmacokinetic profiles, CNS penetration, and enhanced receptor occupancy.     

Bradykinin B1 antagonists: SAR studies in the 2,3-diaminopyridine series

SAR study of the biphenyl region of 2,3-diaminopyridine bradykinin B1 antagonists was investigated with non-aromatic carbo- and heterocyclic rings. A piperidine ring was found to be a good replacement for the proximal phenyl ring while replacement of the distal phenyl was optimal with a cyclohexyl group leading to a dramatic improvement in affinity for the B1 receptor.     

Central administration of peptide and small molecule MC4 receptor antagonists induce hyperphagia in mice and attenuate cytokine-induced anorexia

We investigated the effect of melanocortin 4 receptor (MC4) antagonists on food intake in mice. Food intake during the light phase was significantly increased by ICV administration of mixed MC3/MC4 antagonists (AgRP and SHU9119) or MC4 selective antagonist peptide [(Cyclo (1-5)[Suc-D-Nal-Arg-Trp-Lys]NH2] (MBP10) and the small molecule antagonists THP and NBI-30. Both mixed and selective antagonists significantly reversed anorexia induced by ICV administration of the MC4 agonist (c (1-6) HfRWK-NH2) and the cytokine IL-1beta. These findings provide pharmacological evidence that the MC4 receptor mediates the effects of melanocortin agonists and antagonists on food intake in mice, and support the idea that selective small molecule MC4 antagonists may be useful as therapeutics for cachexia.     

Platelet-activating factor (PAF) receptor antagonists inhibit mitogen-induced human peripheral blood T-cell proliferation

The addition of L-652,731 and L-653,150, two synthetic PAF-specific receptor antagonists, to 72 hour cultures of phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear leukocytes (PBML) caused a dose-dependent inhibition of (3H)-thymidine incorporation into T-cells (IC50: 25 microM and 3.2 microM, respectively). This inhibition was not reversed by exogenous interleukin (IL)-1 and IL-2. PAF receptor antagonists did not affect the expression of IL-2 receptors (TAC-antigen) on T-cells. Exogenous PAF which by itself had no significant effect on PHA-stimulated PBML proliferation, only partially reversed the inhibition of proliferation caused by PAF receptor antagonists. These results may suggest the involvement of endogenously produced PAF in the regulation of immune reactions.     

Bradykinin receptor gene variant and human physical performance.

Accumulating evidence suggests that athletic performance is strongly influenced by genetic variation. One such locus of influence is the gene for angiotensin-I converting enzyme (ACE), which exhibits a common variant [ACE insertion (I)/deletion (D)]. ACE can drive formation of vasoconstrictor ANG II but preferentially degrades vasodilator bradykinin. The ACE I allele is associated with higher kinin activity. A common gene variant in the kinin beta(2) receptor (B(2)R) exists: the -9 as opposed to +9 allele is associated with higher receptor mRNA expression. We tested whether this variant was associated with the efficiency of muscular contraction [delta efficiency (DE)] in 115 healthy men and women, or with running distance among 81 Olympic standard track athletes. We further sought evidence of biological interaction with ACE I/D genotype. DE was highly significantly associated with B(2)R genotype (23.84 +/- 2.41 vs. 24.25 +/- 2.81 vs. 26.05 +/- 2.26% for those of +9/+9 vs. +9/-9 vs. -9/-9 genotype; n = 25, 61, and 29, respectively; P = 0.0008 for ANOVA adjusted for sex). There was evidence for interaction with ACE I/D genotype, with individuals who were ACE II, with B(2)R -9/-9 having the highest DE at baseline. The ACE I/B(2)R -9 "high kinin receptor activity" haplotype was significantly associated with endurance (predominantly aerobic) event among elite athletes (P = 0.003). These data suggest that common genetic variation in the B(2)R is associated with efficiency of skeletal muscle contraction and with distance event of elite track athletes and that at least part of the associations of ACE and fitness phenotypes is through elevation of kinin activity.     

Narcotic antagonists attenuate drinking induced by water deprivation in a primate

Pure narcotic antagonists such as naloxone and naltrexone have consistently been shown to attenuate drinking in the rat after periods of water deprivation. One objective of this study was to extend observations to a primate species, the squirrel monkey. Whereas naloxone and naltrexone have a greater relative affinity for opiate receptors preferentially binding morphine and other opiate alkaloids than for those with high affinity for the endogenous opioid peptides, diprenorphine, another pure opiate antagonist, binds with equally high affinity to both receptor subtypes. Therefore, a second objective was to determine the actions of diprenorphine on drinking in water-deprived rats and squirrel monkeys and to compare the effects of this drug to those of naloxone and naltrexone. All three narcotic antagonists suppressed water consumption of monkeys and rats deprived of water for 18 and 24 hr, respectively. Diprenorphine was the most potent compound tested in both species, producing significant reductions in water consumption of monkeys and rats at systemic doses as low as 0.01 and 0.1 mg/kg respectively. Moreover, diprenorphine was the longest acting of the three drugs in the monkey. These results demonstrate that the narcotic antagonists attenuate drinking in primates as well as in rodents and support the hypothesis that these drugs reduce water intake by interrupting the activity of endogenous opioid pathways mediating drinking behavior.     

Selective orexin receptor antagonists

The orexin, or hypocretin, neuropeptides (orexin-A and orexin-B) are produced on neurons in the hypothalamus which project to key areas of the brain that control sleep–wake states, modulation of food intake, panic, anxiety, emotion, reward and addictive behaviors. These neuropeptides exert their effects on a pair of G-protein coupled receptors termed the orexin-1 (OX1) and orexin-2 (OX2) receptors. Emerging biology suggests the involvement of these receptors in psychiatric disorders as they are thought to play a key role in the regulation of multiple systems. This review is intended to highlight key selective OX1 or OX2 small-molecule antagonists.     

Thiophene-based vitronectin receptor antagonists

A series of alpha(v)beta(3) antagonists based on a thiophene scaffold were synthesized via two routes and evaluated for in vitro biological activity. We have identified several structurally similar antagonists with different selectivities towards alpha(IIb)beta(3), alpha(v)beta(5) and alpha(5)beta(1) at the cellular level. In addition, these antagonists exerted an antiangiogenic effect in the chick chorioallantoic membrane (CAM) assay.     

Bradykinin increases resensitization of purinergic receptor signaling in glioma cells

Background  

Purinergic receptor-mediated signaling plays an important role in the function of glial cells, including glial tumor cells. Bradykinin is also an important paracrine mediator which is highly expressed in brain tumors and may correlate with their pathological grade. Interaction between bradykinin and purinergic signaling may therefore be involved in the regulation of glial tumor cells.