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Full Agonist (full + agonist)
Selected AbstractsConstruction of Arene-Fused-Piperidine Motifs by Asymmetric Addition of 2-Trityloxymethylaryllithiums to Nitroalkenes: The Asymmetric Synthesis of a Dopamine D1 Full Agonist, A-86929.CHEMINFORM, Issue 23 2004Mitsuaki Yamashita Abstract For Abstract see ChemInform Abstract in Full Text. [source] Pharmacology of the Selective 5-HT1B/1D Agonist FrovatriptanHEADACHE, Issue 2002M.B. Comer BSc Objective.,To determine the pharmacological profile of frovatriptan. Background.,Frovatriptan is a new 5-HT1B/1D agonist developed for the treatment of migraine. Methods.,Pharmacological studies were performed using in vitro and in vivo techniques. Results.,Radioligand-binding studies showed that frovatriptan has a high affinity for 5-HT1B and 5-HT1D receptors, and moderate affinity for 5-HT1A, 5-HT1F, and 5-HT7 receptors. In vitro, frovatriptan acts as a potent full agonist at human cloned 5-HT1B and 5-HT1D receptors, and as a moderately potent full agonist at 5-HT7 receptors. Studies of frovatriptan in isolated human arteries demonstrated a lower threshold for constriction of cerebral than coronary vasculature and a bell-shaped dose-response curve was apparent in the coronary arteries. In anesthetized dogs, frovatriptan administration produced no measurable effect on cardiac function or on blood pressure. Frovatriptan had no effects on coronary blood flow following transient coronary artery occlusion, whereas sumatriptan produced a prolonged and significant decrease in coronary blood flow. Conclusion.,The pharmacology of frovatriptan suggests that it should be an effective agent for the acute treatment of migraine, with a low potential for undesirable peripheral effects. [source] Characterization of a glycine receptor domain that controls the binding and gating mechanisms of the ,-amino acid agonist, taurineJOURNAL OF NEUROCHEMISTRY, Issue 3 2001Nian-Lin R. Han The ,-amino acid, taurine, is a full agonist of the human glycine receptor ,1 subunit when recombinantly expressed in a mammalian (HEK293) cell line, but a partial agonist of the same receptor when expressed in Xenopus oocytes. Several residues in the Ala101,Thr112 domain have previously been identified as determinants of ,-amino acid binding and gating mechanisms in Xenopus oocyte-expressed receptors. The present study used the substituted cysteine accessibility method to investigate the role of this domain in controlling taurine-specific binding and gating mechanisms of glycine receptors recombinantly expressed in mammalian cells. Asn102 and Glu103 are identified as taurine and glycine binding sites, whereas Ala101 is eliminated as a possible binding site. The N102C mutation also abolished the antagonistic actions of taurine, indicating that this site does not discriminate between the putative agonist- and antagonist-bound conformations of ,-amino acids. The effects of mutations from Lys104,Thr112 indicate that the mechanism by which this domain controls ,-amino acid-specific binding and gating processes differs substantially depending on whether the receptor is expressed in mammalian cells or Xenopus oocytes. Thr112 is the only domain element in mammalian cell-expressed GlyRs which was demonstrated to discriminate between glycine and taurine. [source] (+)- and (-)- cis -2-Aminomethylcyclopropanecarboxylic Acids Show Opposite Pharmacology at Recombinant ,1 and ,2 GABAC ReceptorsJOURNAL OF NEUROCHEMISTRY, Issue 6 2000Rujee K. Duke Abstract: The effects of the enantiomers of (±)-CAMP and(±)-TAMP [(±)- cis - and(±)- trans -2-aminomethylcyclopropanecarboxylic acids,respectively], which are cyclopropane analogues of GABA, were tested onGABAA and GABAC receptors expressed in Xenopuslaevis oocytes using two-electrode voltage clamp methods. (+)-CAMP wasfound to be a potent and full agonist at homooligomeric GABACreceptors (KD,40 ,M andImax,100% at ,1;KD,17 ,M and Imax,100% at ,2) but a very weak antagonist at,1,2,2L GABAAreceptors. In contrast, (-)-CAMP was a very weak antagonist at both,1,2,2L GABAAreceptors and homooligomeric GABAC receptors (IC50,900 ,M at ,1 and ,400 ,M at,2). Furthermore, (+)-CAMP appears to be a superior agonist tothe widely used GABAC receptor partial agonistcis -4-aminocrotonic acid (KD,74,M and Imax,78% at ,1;KD,70 ,M and Imax,82% at ,2). (-)-TAMP was the most potent of thecyclopropane analogues on GABAC receptors (KD,9 ,M and Imax,40% at,1; KD,3 ,M andImax,50-60% at ,2), but it was also amoderately potent GABAA receptor partial agonist(KD,50-60 ,M and Imax,50% at ,1,2,2LGABAA receptors). (+)-TAMP was a less potent partial agonist atGABAC receptors (KD,60 ,M andImax,40% at ,1; KD,30 ,M and Imax,60% at,2) and a weak partial agonist at,1,2,2L GABAAreceptors (KD,500 ,M andImax,50%). None of the isomers of (±)-CAMP and(±)-TAMP displayed any interaction with GABA transport at theconcentrations tested. Molecular modeling based on the present resultsprovided new insights into the chiral preferences for either agonism orantagonism at GABAC receptors. [source] Differential effects of lorazepam on sleep and activity in C57BL/6J and BALB/cJ strain miceJOURNAL OF SLEEP RESEARCH, Issue 3 2009XIANGDONG TANG Summary Compared to C57BL/6 mice, BALB/c mice exhibit greater ,anxiousness' on behavioural tests of anxiety, and can show significantly longer sleep disruptions after exposure to anxiogenic situations. Relative to C57BL/6 mice, BALB/c mice also have reduced benzodiazepine (BZ) receptor densities in the brain and fivefold less BZ receptor density in the amygdala, a region important in anxiety and in the control of arousal. Lorazepam is a BZ receptor full agonist and has been used to treat both anxiety and insomnia. Differences between C57BL/6 and BALB/c mice raise the question of whether BZ agonists would impact sleep and activity differentially in the two strains. We examined the effects of two doses of lorazepam (0.5 and 1.5 mg kg,1) or saline alone (0.2 mL) on sleep and activity in C57BL/6 (n = 8) and BALB/c (n = 7) mice. Compared to saline, both doses of lorazepam significantly increased non-rapid eye movement (NREM) and reduced activity in both strains. In C57BL/6 mice, rapid eye movement (REM) was increased at both doses. In BALB/c mice, the 0.5 mg kg,1 dose had no significant influence on REM, whereas REM was reduced significantly after the 1.5 mg kg,1 dose. The results demonstrate significant differences between C57BL/6 and BALB/c mice in the effects of lorazepam on REM, whereas the effects on NREM and activity were similar. Strain differences in the number of BZ receptors in the amygdala, but not other brain regions, suggests possible site specificity in the effects of lorazepam on REM. These differences in BZ-binding sites in the amygdala could be a significant factor in differences in the sleep response between C57 and BALB/c mice. [source] Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligandBIOFACTORS, Issue 1 2009Takayuki Sugiura Abstract 2-Arachidonoylglycerol is an arachidonic acid-containing monoacylglycerol isolated from the rat brain and canine gut as an endogenous ligand for the cannabinoid receptors (CB1 and CB2). 2-Arachidonoylglycerol binds to both the CB1 receptor, abundantly expressed in the nervous system, and the CB2 receptor, mainly expressed in the immune system, with high affinity, and exhibits a variety of cannabimimetic activities. Notably, anandamide, another endogenous ligand for the cannabinoid receptors, acts as a partial agonist at these cannabinoid receptors, whereas 2-arachidonoylglycerol acts as a full agonist. The results of structure-activity relationship experiments strongly suggested that 2-arachidonoylglycerol rather than anandamide is the true natural ligand for both the CB1 and the CB2 receptors. Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays physiologically and pathophysiologically essential roles in various mammalian tissues and cells. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] The long-acting ,-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009Anne-Marie Scola Background and purpose:, The long-acting ,2 -adrenoceptor agonist, indacaterol, has been developed as a bronchodilator for the therapeutic management of respiratory diseases. The aim of the present study was to determine whether indacaterol has any anti-inflammatory activity. To this end, the effects of indacaterol on human lung mast cell responses were investigated. Experimental approach:, The effects of indacaterol, and the alternative long-acting ,-agonists formoterol and salmeterol, were investigated on the IgE-dependent release and generation of histamine, cysteinyl-leukotrienes and prostaglandin D2 from human lung mast cells. Moreover, the extent to which long-term (24,72 h) incubation of mast cells with long-acting ,-agonists impaired the subsequent ability of ,-agonists to inhibit mast cell responses was assessed. Key results:, Indacaterol was as potent and as efficacious as the full agonist, isoprenaline (EC50, ,4 nmol·L,1), at inhibiting the IgE-dependent release of histamine from mast cells. Formoterol was a full agonist whereas salmeterol was a partial agonist as inhibitors of histamine release. All three long-acting ,-agonists were effective inhibitors of the IgE-dependent generation of cysteinyl-leukotrienes and prostaglandin D2. Long-term incubation of mast cells with long-acting ,-agonists led to a reduction in the subsequent ability of ,-agonists to stabilize mast cell responses. This tendency to induce functional desensitization was least evident for indacaterol. Conclusions and implications:, Indacaterol is an effective inhibitor of the release of mediators from human lung mast cells. This suggests that, as well as bronchodilation, mast cell stabilization may constitute an additional therapeutic benefit of indacaterol. [source] Virodhamine relaxes the human pulmonary artery through the endothelial cannabinoid receptor and indirectly through a COX productBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2008H Koz, owska Background and purpose: The endocannabinoid virodhamine is a partial agonist at the cannabinoid CB1 receptor and a full agonist at the CB2 receptor, and relaxes rat mesenteric arteries through endothelial cannabinoid receptors. Its concentration in the periphery exceeds that of the endocannabinoid anandamide. Here, we examined the influence of virodhamine on the human pulmonary artery. Experimental approach: Isolated human pulmonary arteries were obtained during resections for lung carcinoma. Vasorelaxant effects of virodhamine were examined on endothelium-intact vessels precontracted with 5-HT or KCl. Key results: Virodhamine, unlike WIN 55,212-2, relaxed 5-HT-precontracted vessels concentration dependently. The effect of virodhamine was reduced by endothelium denudation, two antagonists of the endothelial cannabinoid receptor, cannabidiol and O-1918, and a high concentration of the CB1 receptor antagonist rimonabant (5 ,M), but only slightly attenuated by the NOS inhibitor L -NAME and not affected by a lower concentration of rimonabant (100 nM) or by the CB2 and vanilloid receptor antagonists SR 144528 and capsazepine, respectively. The COX inhibitor indomethacin and the fatty acid amide hydrolase inhibitor URB597 and combined administration of selective blockers of small (apamin) and intermediate and large (charybdotoxin) conductance Ca2+ -activated K+ channels attenuated virodhamine-induced relaxation. The vasorelaxant potency of virodhamine was lower in KCl- than in 5-HT-precontracted preparations. Conclusions and implications: Virodhamine relaxes the human pulmonary artery through the putative endothelial cannabinoid receptor and indirectly through a COX-derived vasorelaxant prostanoid formed from the virodhamine metabolite, arachidonic acid. One or both of these mechanisms may stimulate vasorelaxant Ca2+ -activated K+ channels. British Journal of Pharmacology (2008) 155, 1034,1042; doi:10.1038/bjp.2008.371; published online 22 September 2008 [source] Desensitisation of mast cell ,2 -adrenoceptor-mediated responses by salmeterol and formoterolBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2004Anne-Marie Scola The long-acting ,2 -adrenoceptor agonist formoterol (10,10,10,6M) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective , -adrenoceptor agonist isoprenaline. By contrast, the long-acting ,2 -adrenoceptor agonist salmeterol (10,10,10,6M) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. Isoprenaline, formoterol and salmeterol (all at 10,5M) increased total cell cAMP levels in mast cells over basal by 361±90 (P<0.05), 321±89 (P<0.05) and 64±24% (P>0.05), respectively. Long-term (24 h) incubation of mast cells with formoterol (10,6M) or salmeterol (10,6M) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10,6M) or the short-acting ,2 -adrenoceptor agonist salbutamol (10,6M). The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for ,2 -adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E2, a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. Radioligand binding studies were performed to determine ,2 -adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10,6M) reduced ,2 -adrenoceptor density by 13±5 (P>0.05), 49±13 (P<0.05) and 35±17% (P>0.05), respectively. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to ,2 -adrenoceptor-mediated responses in mast cells. British Journal of Pharmacology (2004) 141, 163,171. doi:10.1038/sj.bjp.0705599 [source] The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1)BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2000D Smart The endogenous cannabinoid anandamide was identified as an agonist for the recombinant human VR1 (hVR1) by screening a large array of bioactive substances using a FLIPR-based calcium assay. Further electrophysiological studies showed that anandamide (10 or 100 ,M) and capsaicin (1 ,M) produced similar inward currents in hVR1 transfected, but not in parental, HEK293 cells. These currents were abolished by capsazepine (1 ,M). In the FLIPR anandamide and capsaicin were full agonists at hVR1, with pEC50 values of 5.94±0.06 (n=5) and 7.13±0.11 (n=8) respectively. The response to anandamide was inhibited by capsazepine (pKB of 7.40±0.02, n=6), but not by the cannabinoid receptor antagonists AM630 or AM281. Furthermore, pretreatment with capsaicin desensitized the anandamide-induced calcium response and vice versa. In conclusion, this study has demonstrated for the first time that anandamide acts as a full agonist at the human VR1. British Journal of Pharmacology (2000) 129, 227,230; doi:10.1038/sj.bjp.0703050 [source] Clinical issues in using buprenorphine in the treatment of opiate dependenceDRUG AND ALCOHOL REVIEW, Issue 3 2000Dr A. Chadderton MB Abstract This paper looks at the current role of buprenorphine in the treatment of opiate dependence. It suggests that buprenorphine is a useful alternative to methadone and that in at least some cases it may be the preferred option. Buprenorphineis a partial agonist and a partial antagonist with a ceiling of opiate activity probably approximately equal to 30mg methadone. It achieves this at a dose of 10-12mg, although there is considerable individual variation. Because of its ceiling effect it has a good safety profile compared to full agonists such as methadone although some overdose deaths, particularly in conjunction with benzodiazepine abuse, have been reported in France. Induction of buprenorphine may take slightly longer than for methadone and there is a higher dropout rate compared to methadone in the first 2 weeks. This is probably due to the antagonist action of buprenorphine causing more withdrawal symptoms in comparison to methadone. Also, the ceiling effect for buprenorphine means that some clients do not experience sufficient opiate activity to satisfy them. Buprenorphine has a long half-life and dissociates slowly from opiate receptors. Most clients can be dosed second-daily but some find this unacceptable due to mood swings and/or withdrawal symptomson the second day. For these clients daily dosing is required. Transferring from buprenorphine to methadone is straightforward and well tolerated by clients. Transferring from methadone to buprenorphine, however, is more difficult because of the partial antagonist action of buprenorphine. Clients experience withdrawal symptoms that can take up to 2 weeks to settle. Most clients find these symptoms unacceptable when transferring from doses of over 30mg of methadone. The optimum method for transferring from methadone to buprenorphine is still to be determined. Withdrawal from buprenorphine appears to be relatively easier than from methadone. This is presumably due to buprenorphine's partial agonist effect at mureceptors. It is expected that during 2000 buprenorphine will be approved for use in Australia for the treatment of opiate dependence. It may well becomea first-line choice for opiate replacement in heroin dependence. It is also likely to be useful in assisting detoxification fromboth methadone and heroin. [source] Interaction between halogenated aromatic compounds in the Ah receptor signal transduction pathwayENVIRONMENTAL TOXICOLOGY, Issue 5 2004Guosheng Chen Abstract Many toxic and biochemical responses to halogenated aromatic compounds (HACs) such as polychlorinated biphenyls (PCBs) and polychlorinated dibenzo- p -dioxins (PCDDs) are mediated through the aryl hydrocarbon receptor (AhR), which is an intracellular cytosolic target for HACs. Environmental exposure to HACs almost always involves complex mixtures of congeners, some of which can antagonize the action of potent HACs such as 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). In this work we studied TCDD and representative PCB congeners, alone and in mixture, for their effect on CYP1A gene transcription and protein levels in primary rat hepatocytes. Together with our previous work, our results suggest that formation of the Ah receptor-ligand-DRE (dioxin response element) complex is the principal point of divergence in the mechanism between an AhR agonist and an AhR antagonist. The coplanar PCBs 77 and 126 and the mono- ortho PCB 156 were full agonists toward CYP1A1 gene transcription and CYP1A protein levels, showing typical additive behavior with TCDD to the target molecule AhR. In contrast, the nonplanar PCB 153 antagonized the action of TCDD, even at concentrations that occupied a significant fraction of AhR molecules. Competitive inhibition explains the commonly reported decrease of ethoxyresorufin- O -deethylase (EROD) activity when PCBs are present in high concentrations and the antagonism of PCBs to the EROD activity of TCDD. The result is that Western blotting offers a much more reliable measure of CYP1A protein concentration than does the EROD assay, despite the greater convenience of the latter. © 2004 Wiley Periodicals, Inc. Environ Toxicol 19: 480,489, 2004. [source] Acute sleep-promoting action of the melatonin agonist, ramelteon, in the ratJOURNAL OF PINEAL RESEARCH, Issue 2 2008Simon P. Fisher Abstract:, Insomnia, which is severe enough to warrant treatment, occurs in ,10% of the general population. It is associated with a range of adverse consequences for human health, economic productivity and quality of life. In animal and human studies, administration of melatonin has been reported to promote sleep, although there has been controversy regarding its effectiveness. The present study used a chronically implanted radiotelemetry transmitter to record electroencephalogram (EEG) and electromyogram (EMG) to enable discrimination of wake (W), nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in un-restrained rats. The acute action of melatonin and ramelteon, a melatonin agonist recently approved for long-term treatment of insomnia in the USA, was examined. Radioligand binding assays on recombinant human MT1/MT2 receptors showed that both the melatonin and ramelteon were both high affinity, nonsubtype selective ligands. Both compounds acted as potent full agonists on a cellular model of melatonin action, the pigment aggregation response in Xenopus laevis melanophores. Both melatonin and ramelteon (10 mg/kg, i/p), administered close to the mid-point of the dark phase of the L:D cycle, significantly reduced NREM sleep latency (time from injection to the appearance of NREM sleep). Both the drugs also produced a short-lasting increase in NREM sleep duration, but the NREM power spectrum was unaltered. Neither drug altered REM latency, REM sleep duration nor power spectrum during REM sleep. In conclusion, ramelteon administration, like melatonin, exerted an acute, short-lasting sleep-promoting effect in the rat, the model most commonly used to evaluate the activity of novel hypnotic drugs. [source] ,-Opioid Receptor Redistribution in the Locus Coeruleus Upon Precipitation of Withdrawal in Opiate-Dependent RatsTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 3 2009Jillian L. Scavone Abstract Administration of ,-opioid receptor (MOR) agonists is known to produce adaptive changes within noradrenergic neurons of the rat locus coeruleus (LC). Alterations in the subcellular distribution of MOR have been shown to occur in the LC in response to full agonists and endogenous peptides; however, there is considerable debate in the literature whether trafficking of MOR occurs after chronic exposure to the partial-agonist morphine. In the present study, we examined adaptations in MOR after chronic opioid exposure using immunofluorescence and electron microscopy (EM), using receptor internalization as a functional endpoint. MOR trafficking in LC neurons was characterized in morphine-dependent rats that were given naltrexone at a dose known to precipitate withdrawal. After chronic morphine exposure, a subtle redistribution of MOR immunoreactivity from the membrane to the cytosol was detected within dendrites of LC neurons. Interestingly, an acute injection of naltrexone in rats exposed to chronic morphine produced a robust internalization of MOR, whereas administration of naltrexone failed to do so in naïve animals. These findings provide anatomical evidence for modified regulation of MOR trafficking after chronic morphine treatment in brain noradrenergic neurons. Adaptations in the MOR signaling pathways that regulate internalization may occur as a consequence of chronic treatment and precipitation of withdrawal. Mechanisms underlying this effect might include differential MOR regulation in the LC, or downstream effects of withdrawal-induced enkephalin (ENK) release from afferents to the LC. Anat Rec, 292:401,411, 2009. © 2009 Wiley-Liss, Inc. [source] Non-prostanoid prostacyclin mimetics as neuronal stimulants in the rat: comparison of vagus nerve and NANC innervation of the colonBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000John A Rudd The spontaneous activity of the rat isolated colon is suppressed by prostacyclin analogues such as cicaprost (IC50=4.0 nM). Activation of prostanoid IP1 -receptors located on NANC inhibitory neurones is involved. However, several non-prostanoids, which show medium to high IP1 agonist potency on platelet and vascular preparations, exhibit very weak inhibitory activity on the colon. The aim of the study was to investigate this discrepancy. Firstly, we have demonstrated the very high depolarizing potency of cicaprost on the rat isolated vagus nerve (EC50=0.23 nM). Iloprost, taprostene and carbacyclin were 7.9, 66, and 81 fold less potent than cicaprost, indicating the presence of IP1 as opposed to IP2 -receptors. Three non-prostanoid prostacyclin mimetics, BMY 45778, BMY 42393 and ONO-1301, although much less potent than cicaprost (195, 990 and 1660 fold respectively), behaved as full agonists on the vagus nerve. On re-investigating the rat colon, we found that BMY 45778 (0.1,3 ,M), BMY 42393 (3 ,M) and ONO-1301 (3 ,M) behaved as specific IP1 partial agonists, but their actions required 30,60 min to reach steady-state and only slowly reversed on washing. This profile contrasted sharply with the rapid and readily reversible contractions elicited by a related non-prostanoid ONO-AP-324, which is an EP3 -receptor agonist. The full versus partial agonism of the non-prostanoid prostacyclin mimetics may be explained by the markedly different IP1 agonist sensitivities of the two rat neuronal preparations. However, the slow kinetics of the non-prostanoids on the NANC system of the colon remain unexplained, and must be taken into account when characterizing neuronal IP-receptors. British Journal of Pharmacology (2000) 129, 782,790; doi:10.1038/sj.bjp.0703090 [source] The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1)BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2000D Smart The endogenous cannabinoid anandamide was identified as an agonist for the recombinant human VR1 (hVR1) by screening a large array of bioactive substances using a FLIPR-based calcium assay. Further electrophysiological studies showed that anandamide (10 or 100 ,M) and capsaicin (1 ,M) produced similar inward currents in hVR1 transfected, but not in parental, HEK293 cells. These currents were abolished by capsazepine (1 ,M). In the FLIPR anandamide and capsaicin were full agonists at hVR1, with pEC50 values of 5.94±0.06 (n=5) and 7.13±0.11 (n=8) respectively. The response to anandamide was inhibited by capsazepine (pKB of 7.40±0.02, n=6), but not by the cannabinoid receptor antagonists AM630 or AM281. Furthermore, pretreatment with capsaicin desensitized the anandamide-induced calcium response and vice versa. In conclusion, this study has demonstrated for the first time that anandamide acts as a full agonist at the human VR1. British Journal of Pharmacology (2000) 129, 227,230; doi:10.1038/sj.bjp.0703050 [source] Characterization of New PPAR, Agonists: Analysis of Telmisartan's Structural ComponentsCHEMMEDCHEM, Issue 3 2009Matthias Goebel Abstract Telmisartan was originally designed as an AT1 antagonist but was later also characterized as a selective PPAR, modulator. This study focused on the identification of the essential structural motifs of telmisartan for PPAR, activation activity, elucidating the individual SAR of each different component (shown). In addition to a proven efficacy in lowering blood pressure, the AT1 receptor blocker telmisartan has recently been shown to exert pleiotropic effects as a partial agonist of the nuclear peroxisome proliferator-activated receptor gamma (PPAR,). Based on these findings and an excellent side-effect profile, telmisartan may serve as a lead structure for the development of new PPAR, ligands. Therefore, we analyzed the structural components of telmisartan to identify those necessary for PPAR, activation. Synthesized compounds were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPAR,DEF, pGal5-TK-pGL3 and pRL-CMV. The data obtained in this structure,activity relationship (SAR) study provide the basis for the development of new PPAR, ligands, which could lead to active compounds with a distinct, beneficial pharmacological profile compared with the existing full agonists. The basic 1-(biphenyl-4-ylmethyl)-1H -benzimidazole scaffold of telmisartan was identified as an essential moiety with either a carboxylic acid or tetrazole group at the C-2 position of the biphenyl. For maximum potency and activity, the alkyl chain in position 2 requires a minimum length of at least two C atoms (ethyl group), while the methyl group at position 4 of the benzimidazole core seems to contribute to partial activity. An additional benzimidazole at position 6 appears to be a further determinant of potency. Similar conclusions can be drawn for the methyl group in position 1. [source] | ||||||||||||||||