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Antagonist Potency (antagonist + potency)

Distribution by Scientific Domains

Medical Sciences	71%
Chemistry	28%

Selected Abstracts

Synthesis and Biological Evaluation of 14-Alkoxymorphinans.

HELVETICA CHIMICA ACTA, Issue 7 2003
Part 1
The 14- O -benzylnaltrexones 3,6 were prepared from naltrexone (2) in several steps. The novel compounds were biologically evaluated in radioligand binding and in [35S]GTP,S functional assays in comparison to the reference compound naltrexone. In the binding assay, compounds 3,6 exhibited preference for , opioid receptors, while the parent compound naltrexone shows preference for , receptors. In the functional assay, , antagonist potency of compounds 3,6 was in the range of naltrexone, while , antagonist potency was considerably higher for most novel compounds in comparison to naltrexone. [source]

AL-3138 Antagonizes FP Prostanoid Receptor-mediated Inositol Phosphates Generation: Comparison with Some Purported FP Antagonists

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2000
N. A. SHARIF
The aim of this study was to pharmacologically characterize the antagonist properties of a novel prostaglandin F2, (PGF2,) analogue (11-deoxy-16-fluoro PGF2,; AL-3138) using a variety of second-messenger assays of prostaglandin receptor subtypes. A detailed comparison was made between AL-3138 and some purported FP receptor antagonists such as PGF2, dimethylamine, PGF2, dimethylamide, glibenclamide and phloretin using the FP receptor-mediated phosphoinositide turnover assay in A7r5 rat thoracic aorta smooth muscle cells and mouse Swiss 3T3 fibroblasts. The potency and efficacy of AL-3138 as an FP receptor agonist were: EC50 = 72.2 ± 17.9 nM (Emax = 37%) (n = 3) in A7r5 cells and EC50 = 20.5 ± 2.8 nM (Emax = 33%) (n = 5) in 3T3 cells. Being a partial agonist, the antagonist potency of AL-3138 against fluprostenol in A7r5 cells was determined to be: Ki = 296 ± 17 nM (n = 3) and Kb = 182 ± 44nM (n = 5) (-log Kb = 6.79 ± 0.1). AL-3138 exhibited very minimal or no antagonistic effects at EP2, EP4, DP and TP prostaglandin receptors. Both PGF2, dimethylamide and PGF2, dimethylamine were inactive as FP receptor antagonists, whereas phloretin and glibenclamide were very weak and had -log Kb values of 5.28 ± 0.09 (n = 3) and 3.58 ± 0.32 (n = 3), respectively. However, phloretin antagonized functional responses of EP2 and DP prostanoid receptors, and also the V1 , vasopressin receptor. AL-3138 competed for [3H]PGF2, binding to FP receptors with a relatively high affinity (IC50high = 312 ± 95nM) matching its functional antagonist potency. In conclusion, AL-3138 is a more potent and selective FP receptor antagonist than glibenclamide, phloretin, PGF2, dimethylamide and PGF2, dimethylamine and is therefore a unique and novel pharmacological tool to help characterize FP receptor-mediated functions. [source]

Cloning and pharmacological characterization of the equine adenosine A2A receptor: a potential therapeutic target for the treatment of equine endotoxemia

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2006
C. I. BRANDON
The aim of the current study was to clone the equine adenosine A2A receptor gene and to establish a heterologous expression system to ascertain its pharmacologic profile via radioligand binding and functional assays. An eA2A -R expression construct was generated by ligation of the eA2A cDNA into the pcDNA3.1 expression vector, and stably transfected into human embryonic kidney cells (HEK). Binding assays identified those clones expressing the eA2A -R, and equilibrium saturation isotherm experiments were utilized to determine dissociation constants (KD), and receptor densities (Bmax) of selected clones. Equilibrium competition binding revealed a rank order of agonist potency of ATL > CV-1808 > NECA > 2-CADO > CGS21680, and a rank order of antagonist potency as ZM241385 > 8-phenyltheophylline > p -sulfophenyltheophylline > caffeine. Furthermore, adenylate cyclase assays using selective A2A -R agonists revealed that the eA2A -R functionally coupled to G,s as indicated by an increase in intracellular [3H]cAMP upon receptor activation. Finally, NF- ,B reporter gene assays revealed a CGS21680 concentration-dependent inhibition of NF- ,B activity. These results indicate that the heterologously expressed eA2A -R has a pharmacological profile similar to that of other mammalian A2A receptors and thus can be utilized for further characterization of the eA2A -R to ascertain whether it can serve as a suitable pharmacological target for equine inflammatory disease. [source]

Pharmacological characterization of ,2 -adrenoceptor-mediated responses in pig nasal mucosa

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2003
M. R. Corboz
Summary 1 Pig nasal mucosal strips were incubated with ,-adrenoceptor antagonists followed by ,2 -adrenoceptor agonist concentration,response curves. 2 Contractions elicited by the ,2 -adrenoceptor agonists BHT-920 (pD2 = 6.16 ± 0.07), UK 14,304 (pD2 = 6.89 ± 0.13) and PGE-6201204 (pD2 = 7.12 ± 0.21) were blocked by the ,2 -adrenoceptor antagonist yohimbine (0.1 ,m). In contrast, the ,1 -adrenoceptor antagonist prazosin (0.03 ,m) had no effect on the BHT-920-, UK 14,304- and PGE-6201204-induced contractions, but blocked the contractile response to the ,1 -adrenoceptor agonist phenylephrine (pD2 = 5.38 ± 0.04) and the mixed ,1 - and ,2 -adrenoceptor agonist oxymetazoline (pD2 = 6.30 ± 0.22). 3 The ,2 -adrenoceptor antagonist yohimbine (0.01,0.1 ,m, pA2 = 8.04), ,2B/C -adrenoceptor antagonist ARC 239 (10 ,m, pKb = 6.33 ± 0.21), ,2A/C -adrenoceptor antagonist WB 4101 (0.3 ,m, pKb = 8.01 ± 0.24), ,2A -adrenoceptor antagonists BRL44408 (0.1 ,m, pKb = 6.82 ± 0.34) and RX 821002 (0.1 ,m, pKb = 8.31 ± 0.35), ,2C -adrenoceptor antagonists spiroxatrine (1 ,m, pKb = 7.32 ± 0.32), rauwolscine (0.1 ,m, pKb = 8.16 ± 0.14) and HV 723 (0.3 ,m, pKb = 7.68 ± 0.14) inhibited BHT-920-induced contractions in pig nasal mucosa. 4 The present antagonist potencies showed correlations with binding affinity estimates (pKi) obtained for these antagonists at the human recombinant ,2A - and ,2C -adrenoceptors (r = 0.78 and 0.83, respectively) and with binding affinity estimates (pKd) obtained in pig native ,2A - and ,2C -monoreceptor assays (r = 0.85 and 0.78, respectively). No correlation was observed for the ,2B -subtype. 5 In conclusion, contractile responses to phenylephrine, BHT-920, UK 14,304, PGE-6201204 and oxymetazoline indicate that ,1 - and ,2 -adrenoceptors are present and mediate vasoconstriction in pig nasal mucosa. Furthermore, correlation analysis comparing antagonist potency in pig nasal mucosa with affinities for human recombinant ,2 -adrenoceptors and native pig ,2 -adrenoceptors suggest that ,2A - and ,2C -adrenoceptor subtypes constrict pig nasal mucosa vasculature. [source]

The relative importance of the time-course of receptor occupancy and response decay on apparent antagonist potency in dynamic assays

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2000
M. Corsi
1 The potency of the ,1 -adrenoceptor antagonist atenolol was measured as an inhibitor of responses to isoprenaline in guinea-pig left atria. Measurements were made in two ways, firstly, by pre-incubating the atria with a given concentration of atenolol followed by an isoprenaline dose,response curve and, secondly, by measuring the response to isoprenaline followed by addition of atenolol. 2 It was found that the estimation of atenolol potency as an antagonist of ,1 -adrenoceptors by these two methods gave divergent results. Specifically, it was found that the isoprenaline-induced increased rate of myocardial relaxation was resistant to receptor blockade. Thus, the rate-limiting step in the relaxation response was dissociated from receptor activation and therefore, could not be used for the measurement of receptor occupancy. 3 In contrast, the positive inotropic response was very responsive to receptor occupancy. However, when atenolol was used to block a steady-state isoprenaline response, there was a complicating depression of basal inotropy after receptor blockade that obfuscated measurement of receptor blockade. 4 In general, these data indicated that the blockade of a steady-state agonist response to measure the potency of an antagonist might in some cases yield erroneous results. These studies indicate some caution in the interpretation of blockade responses in pre-contracted or pre-stimulated pharmacological preparations. [source]

,,,-Cyclopentaneglycine Dipeptides Capped with Biaryls as Tachykinin NK2 Receptor Antagonists

CHEMMEDCHEM, Issue 7 2008
Marina Porcelloni Dr.
Abstract The NK2 receptor belongs to the family of tachykinin neurotransmitters. It has been reported to be involved in several pathological conditions, and selective antagonists are potentially useful drugs for the treatment of asthma, irritable bowel syndrome, cystitis, and depression. Starting from in-house capped dipeptide libraries, we were able to identify a number of molecules with sub-nanomolar binding affinity for the hNK2 receptor. All were characterized by a rigid core structure with a strong constraint induced by an ,,,-cyclopentaneglycine fragment. Herein we report the further elaboration of three initial basic structures. The planar benzothiophene group was substituted with a series of biphenyl and heterobiphenyl moieties that are well tolerated in terms of receptor affinity. The new compounds also maintained good antagonist potency in an in,vitro functional assay, and a number of them showed significant in,vivo activity after intravenous administration in our guinea pig model. [source]