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Agonistic Activity (agonistic + activity)
Selected AbstractsNew Series of N-Substituted Phenyl Ketone Oxime Ethers: Synthesis and Bovine ,3 -Adrenergic Agonistic Activities.CHEMINFORM, Issue 20 2003A. El Hadri Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: New Series of Aryloxypropanolamines with Both Human ,3 -Adrenoceptor Agonistic Activity and Free Radical Scavenging Properties.CHEMINFORM, Issue 19 2002Silvere Aubriot Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Physiological constraints on contest behaviourFUNCTIONAL ECOLOGY, Issue 4 2007M. BRIFFA Summary 1Contests may involve injurious fighting, other types of direct physical aggression and communication. They occur over ownership access to mates and other resources that may increase an individual's attractiveness and its chance of survival. Traits that enhance resource holding potential may be the result of sexual selection, natural selection or a combination of both. 2Agonistic behaviours are expected to be demanding to perform and costly in terms of changes in physiological state. The ability to meet the physiological costs may determine contest outcomes and constrain the intensity of agonistic activities. 3The energetic costs have been investigated in a broad range of taxa using a variety of techniques. They include the mobilization of energy reserves, but a key cost in several taxa appears to be limited anaerobic capacity and subsequent accumulation of lactic acid. Androgens, stress hormones and neurohormones have also been shown to constrain fighting behaviour. However, due to key differences in the endocrine systems of vertebrates and invertebrates, the effects of hormones are far less consistent across taxa than in the case of metabolites. 4Physiological constraints on fighting may vary according to their importance relative to circumstantial costs, the time-scale over which they exert their effects, their effects on different roles and their causal links with behaviour. Incorporating these factors into theoretical studies of contest behaviour may give further insights of how the costs of fighting influence agonistic behaviour. [source] Development of a potent and selective GPR7 (NPBW1) agonist: a systematic structure,activity study of neuropeptide BJOURNAL OF PEPTIDE SCIENCE, Issue 6 2007Maki Kanesaka Abstract Neuropeptide B (NPB) has been recently identified as an endogenous ligand for GPR7 (NPBW1) and GPR8 (NPBW2) and has been shown to possess a relatively high selectivity for GPR7. In order to identify useful experimental tools to address physiological roles of GPR7, we synthesized a series of NPB analogs based on modification of an unbrominated form of 23 amino acids with amidated C -terminal, Br(,)NPB-23-NH2. We confirmed that truncation of the N -terminal Trp residue resulted in almost complete loss of the binding affinity of NPB for GPR7 and GPR8, supporting the special importance of this residue for binding. Br(,)NPB-23-NH2 analogs in which each amino acid in positions 4, 5, 7, 8, 9, 10, 12 and 21 was replaced with alanine or glycine exhibited potent binding affinity comparable to the parent peptide. In contrast, replacement of Tyr11 with alanine reduced the binding affinity for both GPR7 and GPR8 four fold. Of particular interest, several NPB analogs in which the consecutive amino acids from Pro4 to Val13 were replaced with several units of 5-aminovaleric acid (Ava) linkers retained their potent affinity for GPR7. Furthermore, these Ava-substituted NPB analogs exhibited potent agonistic activities for GPR7 expressed in HEK293 cells. Among the Ava-substituted NPB analogs, analog 15 (Ava-5) and 17 (Ava-3) exhibited potency comparable to the parent peptide for GPR7 with significantly reduced activity for GPR8, resulting in high selectivity for GPR7. These highly potent and selective NPB analogs may be useful pharmacological tools to investigate the physiological and pharmacological roles of GPR7. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structuresACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2009Takuji Oyama Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPAR, and PPAR, LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD,ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPAR, LBD in complex with an ,/,-selective ligand, TIPP-401, and with a related ,-specific ligand, TIPP-204, were also determined. The comparison between the two PPAR, complexes revealed how each ligand exhibits either a `dual selective' or `single specific' binding mode. [source] PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2009Nicoletta Schintu Abstract Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-,). PPAR-, can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-, agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted. [source] Magnesium and biological activity of oxytocin analogues modified on aromatic ring of amino acid in position 2JOURNAL OF PEPTIDE SCIENCE, Issue 8 2001ina Slaninová Abstract For the purpose of evaluating substitution effects in the ortho, meta or para positions of the aromatic ring of tyrosine or phenylalanine in position 2 of oxytocin on uterotonic activity in vitro in the presence and absence of magnesium ions, six new analogues of oxytocin ([,,- and ,,- m -methylphenylalanine2]oxytocin, [,,- and ,,- m -methoxyphenylalanine2]oxytocin and [,,- and ,,- o -methyltyrosine2]oxytocin) were synthesized and several previously described analogues resynthesized. For the phenylalanine series, it is found that, in the absence of magnesium ions, substitution of the ortho and meta positions leads to loss of intrinsic activity (the analogues are antagonists) in contrast to the para position. In the tyrosine series, only methyl substitution in the meta position has this effect (substitution of ortho position only attenuates the agonistic biological activity). Addition of Mg ions restores to a certain degree the agonistic activity in the case of the o -methylphenylalanine analogue and enhances the agonistic activity of o -methyltyrosine oxytocin. All other analogues keep the original qualities as in the absence of Mg. Molecular modelling calculations of the structure of the above analogues was carried out to help explain these findings of the molecular level. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd. [source] Binding and functional affinity of some newly synthesized phenethylamine and phenoxypropanolamine derivatives for their agonistic activity at recombinant human ,3 -adrenoceptorJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2003Maruf Ahmed ABSTRACT ,3 -Adrenoceptor is the predominant ,-adrenoceptor in adipocytes and has drawn much attention during the investigation for anti-obesity and antidiabetes therapeutics. Thirteen new compounds have been evaluated for their potencies and efficacies as ,3 -adrenoceptor agonists on human ,3 - adrenoceptor expressed in COS-7 and Chinese hamster ovary (CHO) cells using radio ligand binding assay and cyclic AMP (cAMP) accumulation assay. Phenoxypropanolamine derivatives, SWR-0334NA (([E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy]acetic acid sodium salt), SWR-0335SA ((E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0342SA (S-(Z)-[4-[[1-[2-[(2-hydroxy,3-phenoxypropyl)]amino]ethyl]-1-pro-penyl]phenoxy] acetic acid ethanedioic acid), SWR-0348SA-SITA ((E)-[4-[5-[(3-phenoxy-2-hydroxy-propyl)amino]-2-hexene,3-yl] phenoxy]acetic acid ethanedioic acid) and SWR-0361SA ((E)-N-methyl-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl]phenoxy]acetoamide ethanedioic acid) showed higher agonistic activity for the ,3 -adrenoceptor. Among the compounds tested, SWR-0334NA exhibited full agonist activity (%Emax = 100.26) despite its lower binding affinity (pK1 = 6.11). Compounds SWR-0338SA((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)amino]-2-pentene,3-yl]phenoxy]acetic acid ethanedioic acid), SWR-0339SA (S-(E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0345HA ((E)-2-methyl,3-[4-[2-(2-phenyl-2-hydroxyethyl-amino)ethoxy] phenyl]-2-propenoic acid ethyl ester hydrochloride), SWR-0358SA ((E)-(2-methoxy-ethyl)-[4-[5-[(3-phenoxy-2-hydroxypropyl) amino]-2-pentene,3-yl]phenoxy]acetoamide ethanedioic acid) and SWR-0362SA ((E)-1-[[[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene ,3-yl]phenoxy]-acetyl]carbonyl]piperidine ethanedioic acid) had moderate agonistic activity and were phenethylamine and phenoxypropanolamine derivatives. Compounds SWR-0065HA ([4-[2-[3-[[(3,4-dihydro-4-oxo-[1,2,4]-triazino(4,5-a)indol)-lyl]oxy]-2-hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR-0098NA ((E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl] phenoxy]-acetic acid sodium salt) and SWR-0302HA ([4-[[4-[2-(3-chlorophenoxy-2-hydroxypropyl)amino]-E-2-butenyl]oxy]phenoxy]acetic acid hydrochloride) had very low binding affinity towards ,3 -adreno-ceptors and they did not induce cAMP accumulation. We concluded that compounds SWR-0334NA, SWR-0335SA, SWR-0342SA, SWR-0348SA-SITA and SWR-0361SA were potential agonists of human ,3 - adrenoceptor. Further investigation on their selectivity towards ,3 -adrenoceptor could be useful for the exploration of the physiological properties of the ,3 -adrenoceptor. [source] Patterns of QT Dispersion in Athletic and Hypertensive Left Ventricular HypertrophyANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 3 2004Laura Maria Lonati M.D. Objective:,The objective of this article is to assess whether left ventricular hypertrophy (LVH) due to physical training or of hypertensive patients shows similarities in QT length and QT dispersion. Methods:,A total of 51 subjects were studied: 17 essential hypertensive patients (27.7 ± 5.6 years), 17 athletes involved in agonistic activity (canoeing) (24.8 ± 6.1 years), and 17 normotensive healthy subjects as control group (24.8 ± 3.6 years). The testing protocol consisted of (1) clinic BP measurement, (2) echocardiography, (3) 12-lead electrocardiographic examination (QT max, QTc max, QT min, QTc min, ,QT, ,QTc). Results:,There were no significant differences between the body surface area, height, and age of the three groups. Clinic blood pressure was higher in hypertensives (146.5 ± 45.2/93.5 ± 4.9 mmHg) versus athletes (120.9 ± 10.8/77.1 ± 6.0 mmHg) and controls (123.5 ± 4.8/78.8 ± 2.9 mmHg) by definition. Indexed left ventricular mass (LVM/BSA) was significantly greater in both athletes (148.9 ± 21.1 g/m2) and hypertensives (117.1 ± 15.2 g/m2) versus controls (81.1 ± 14.5 g/m2; P < 0.01), there being no statistical difference among them. LVH (LVMI > 125 g/m2) was observed in all athletes, while the prevalence in hypertensives was 50%. In spite of this large difference in cardiac structure there were no significant differences in QT parameters between athletes and the control group, while hypertensive patients showed a significant increase in QT dispersion versus the two other groups (,QT 82 ± 2.1, 48 ± 1.3, 49 ± 2.3 ms; P < 0.01; ,QTc 88 ± 2.0, 47 ± 1.4, 54 ± 2.7; P < 0.01). Conclusions:,LVH induced by physical training activity is not associated with an increase in QT dispersion, whereas pathological increase in LVM secondary to hypertension is accompanied by an increased QT dispersion. [source] Novel Fused Pyrrole Heterocyclic Ring Systems as Structure Analogs of LE 300: Synthesis and Pharmacological Evaluation as Serotonin 5-HT2A, Dopamine and Histamine H1 Receptor LigandsARCHIV DER PHARMAZIE, Issue 2 2010Sherif A. F. Rostom Abstract LE 300 represents a structurally novel type of antagonists acting preferentially at the dopamine D1/D5 receptors and the serotonin 5-HT2A receptor. This compound consists of a ten-membered central azecine ring fused to an indole ring on one side and a benzene moiety on the other side. To estimate the importance of the indole and / or phenyl moieties in this highly active benz-indolo-azecine, both rings were removed and replaced with a 1H -pyrrole counterpart. Accordingly, some new analogs of LE 300 namely, pyrrolo[2,3- g]indolizine, pyrrolo[3,2- a]quinolizine rings and their corresponding dimethylpyrrolo[2,3- d]azonine, and dimethylpyrrolo[2,3- d]azecine were synthesized to be evaluated for their activity at the 5-HT2A and dopamine D1, D2L, D4, D5 receptors in relation to LE 300. In addition, their activity at the H1 -histamine receptors was also determined. The results suggested that the rigid pyrrolo[2,3- g]indolizine 7 and pyrrolo[3,2- a]quinolizine 8 analogs lacked biological activity in the adopted three bioassays. However, their corresponding flexible pyrrolo[2,3- d]azonine 11 and pyrrolo[2,3- d]azecine 12 derivatives revealed weak partial agonistic activity and weak antagonistic potency at the serotonin 5-HT2A and histamine H1 receptors, respectively. Meanwhile, they showed no affinity to any of the four utilized dopamine receptors. Variation in ring size did not contribute to a significant influence on the three tested bioactivities. Removal of the hydrophobic moiety (phenyl ring) and replacement of the indole moiety with a 1H -pyrrole counterpart led to a dramatic alteration in the profile of activity of such azecine-type compounds. [source] Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1,-hydroxyvitamin D3 -26,23-lactoneACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2010Shinji Kakuda TEI-9647 antagonizes vitamin D receptor (VDR) mediated genomic actions of 1,,25(OH)2D3 in human cells but is agonistic in rodent cells. The presence of Cys403, Cys410 or of both residues in the C-terminal region of human VDR (hVDR) results in antagonistic action of this compound. In the complexes of TEI-9647 with wild-type hVDR (hVDRwt) and H397F hVDR, TEI-9647 functions as an antagonist and forms a covalent adduct with hVDR according to MALDI,TOF MS. The crystal structures of complexes of TEI-9647 with rat VDR (rVDR), H305F hVDR and H305F/H397F hVDR showed that the agonistic activity of TEI-9647 is caused by a hydrogen-bond interaction with His397 or Phe397 located in helix 11. Both biological activity assays and the crystal structure of H305F hVDR complexed with TEI-9647 showed that the interaction between His305 and TEI-9647 is crucial for antagonist activity. This study indicates the following stepwise mechanism for TEI-9647 antagonism. Firstly, TEI-9647 forms hydrogen bonds to His305, which promote conformational changes in hVDR and draw Cys403 or Cys410 towards the ligand. This is followed by the formation of a 1,4-Michael addition adduct between the thiol (,SH) group of Cys403 or Cys410 and the exo -methylene group of TEI-9647. [source] The First Potent Subtype-Selective Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy-4-isopropylphenylamino Moiety, NEt-3IP (RXR,/,-dual agonist)CHEMMEDCHEM, Issue 5 2008Kayo Takamatsu Abstract Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported an RXR,-preferential agonist 4-[N -methanesulfonyl- N -(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6,a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branched alkoxy groups, 6-[N -ethyl- N -(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IP: 7,a) and 6-[N -ethyl- N -(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB: 7,c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7,a) was found to be the first RXR,/,-selective (or RXR,/,-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7,a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function. [source] | ||||||||||||||||