Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist

Aiyar, Nambi; Baker, Elayne; Vickery-Clark, Lynne M.; Ohlstein, Eliot H.; Gellai, Miklos; Fredrickson, Todd A.; Brooks, David P.; Weinstock, Joseph; Weidley, E. F.; Edwards, Richard M.

doi:10.1016/0014-2999(95)00287-u

Cited by 20 publications

(8 citation statements)

References 12 publications

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“…The duration of antihypertensive action is thought to be related to the inhibitory manner of the non-competitive inhibition; such inhibition is thought to produce a longer effect on the contractile response induced by angiotensin II in vascular preparations in vitro. 15 In in vitro kinetic studies, 17 [ 125 I]angiotensin II dissociated rapidly, with an initial half-time of dissociation (t 1/2 ) of 12 min in adrenal cortical membranes, which is similar to the result of Grossman et al 25 27 Aiyar et al 28 showed that the dissociation rate of SB203220, which exhibits a partial insurmountable antagonism of angiotensin II-induced contraction in rabbit aorta, is slower than that of SK&F108566, a surmountable antagonist. These findings suggest that the insurmountable antagonism caused by candesartan is attributable to its slow dissociation from angiotensin AT 1 receptors.…”

Section: Discussionsupporting

confidence: 69%

Pharmacologic properties of candesartan cilexetil—possible mechanisms of long-acting antihypertensive action

et al. 1999

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Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of

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Section: Discussionsupporting

confidence: 69%

Pharmacologic properties of candesartan cilexetil—possible mechanisms of long-acting antihypertensive action

et al. 1999

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“…In the case of hemi-equilibria, dextral displacement can continue much like competitive antagonism. For example, the AT1 antagonist SB203220 [E-a-[[2-butyl-1-(carboxy-1-naphalenyl)methyl-1H-imidazol-5-yl]-methylene]-2-thiophene-propanic acid] produces a marked depression maximal angiotensin response that reaches a plateau that remains constant through three orders of magnitude of the antagonist (Aiyar et al, 1995). Desensitization of the receptor by the agonist also has been shown to lead to depression of maximal responses.…”

Section: Discussionmentioning

confidence: 99%

Determining the Potency and Molecular Mechanism of Action of Insurmountable Antagonists

Kenakin¹,

Jenkinson²,

Watson³

2006

J Pharmacol Exp Ther

161

138

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Insurmountable antagonism (maximal response to the agonist depressed) can result from a temporal inequilibrium involving a slow offset orthosteric antagonist or be the result of an allosteric modulation of the receptor. The former mechanism is operative when the antagonist, agonist, and receptors cannot come to proper equilibrium during the time allotted for collection of agonist response (hemi-equilibrium conditions). Allosteric effects (changes in the conformation of the receptor through binding of the allosteric modulator to a separate site) can preclude the agonist-induced production of response, leading to depression of maximal responses. In these cases, the effects on receptor affinity can be observed as well. The first premise of this article is that system-independent estimates of insurmountable antagonist potency can be made with no prior knowledge of molecular mechanism through the use of pA 2 (Ϫlog molar concentration of antagonist producing a 2-fold shift of the concentration response curve) measurements The relationship between the pA 2 and antagonist pK B (Ϫlog equilibrium dissociation constant of the antagonist-receptor complex) is described; the former is an extremely close approximation of the latter in most cases. The second premise is that specially designed experiments are required to differentiate orthosteric versus allosteric mechanisms; simply fitting of data to orthosteric or allosteric theoretical models can lead to ambiguous results. A strategy to determine whether the observed antagonism is orthosteric (agonist and antagonist competing for the same binding site on the receptor) or allosteric in nature is described that involves the detection of the hallmarks of allosteric response, namely saturation and probe dependence of effect.Two major considerations in a drug discovery program for antagonists are the need for 1) system-independent estimates of potency and 2) knowledge of the molecular mechanism of action. The former enables systematic study of structure and activity and subsequent optimization of activity, whereas the latter allows prediction of the properties of the antagonist in the therapeutic situation. The major premise of this study is that knowledge of the mechanism of action of insurmountable antagonists is not required for the systemindependent measure of antagonist potency. In fact, verisimilitude of data to specific theoretical models is an unreliable way to determine mechanism of action (vide infra). It will be proposed that specifically designed experiments are required to do so.By definition, antagonists interfere with the ability of agonists to produce pharmacological response. The way they express this interference varies but generally involves changing the location parameter (EC 50 ; molar concentration proArticle, publication date, and citation information can be found at

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“…In this respect, slow receptor dissociation has been proposed to contribute to the long-lasting clinical action of antagonists for angiotensin AT 1 (Wienen et al, 1993;Aiyar et al, 1995;De Arriba et al, 1996;Unger, 1999), histamine H 1 (Anthes et al, 2002), nicotinic (el-Bizri andClarke, 1994), adrenergic ␣ 2A (Kukkonen et al, 1997), serotonergic 5-HT 3 (Blower, 2003), and muscarinic M 3 (Swinney, 2004) receptors. In this respect, recent simulation studies (Vauquelin and Van Liefde, 2006) reveal that, compared with a fast dissociating antagonist, prolonged in vivo receptor occupancy should take place when the antagonistreceptor complexes dissociate much slower than the antagonist gets eliminated.…”

Section: Discussionmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Lindström¹,

Mentzer²,

Påhlman³

et al. 2007

J Pharmacol Exp Ther

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We compared the neurokinin 1 receptor (NK 1 R) antagonists aprepitant, CP-99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-methyl]napthamide]] with respect to receptor interactions and duration of efficacy in vivo. In Ca 2ϩ mobilization assays (fluorometric imaging plate reader), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP). In reversibility studies, antagonists were present for 30 min before washing, and responses to SP were repeatedly measured afterward. The compounds were administered i.p. to gerbils, and the gerbil foot tap (GFT) response was monitored at various time points. The NK 1 R receptor occupancy for aprepitant was determined in striatal regions. Levels of compound in brain and plasma were measured. Antagonists were equipotent at human NK 1 R and acted competitively with SP. After preincubation, aprepitant and ZD6021 attenuated the maximal responses, whereas CP-99994 only shifted the SP concentration-response curve to the right. The inhibitory effect of CP-99994 was over within 30 min, whereas for ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced maximal inhibition lasting at least 60 min. CP-99994 (3 mol/kg) inhibited GFT by 100% 15 min after administration, but the effect declined rapidly together with brain levels thereafter. The efficacy of ZD6021 (10 mol/kg) lasted 4 h and correlated well with brain levels. Aprepitant (3 mol/kg) inhibited GFT and occupied striatal NK 1 R by 100% for Ͼ48 h despite that brain levels of compound were below the limit of detection after 24 h. Slow functional reversibility is associated with long-lasting in vivo efficacy of NK 1 R antagonists, whereas the efficacy of compounds with rapid reversibility is reflected by their pharmacokinetics.The neurokinins substance P (SP), neurokinin (NK) A (NKA), and NKB belong to the tachykinin peptide family (Severini et al., 2002). The tachykinin receptors are divided into three subtypes: NK 1 R, NK 2 R, and NK 3 R. The rank order of potency of the endogenous tachykinins are: for NK 1 R, SP Ն NKA Ͼ NKB; for NK 2 R, NKA Ͼ NKB Ͼ SP; and for NK 3 R, NKB Ͼ NKA Ͼ SP (for review, see Pennefather et al., 2004). Hemokinin-1 and endokinins A and B are relatively new mammalian members of the tachykinin family but appear to have similar receptor pharmacology as SP (Page, 2006). On the other hand, endokinins C and D have negligible affinity for known NK receptors (Page, 2006).Preclinical research has implicated especially the NK 1 R as being involved in several pathological disorders, including emesis, asthma, psychiatric disorders, gastrointestinal disorders, pain, migraine, inflammation, and urinary bladder disorders. This has led to the subsequent development of selective and potent NK 1 R antagonists (for recent review, see Quartara and Altamura, 2006). However, so far, only aprepitant has reached the market for treatment of chemothe...

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Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist

Cited by 20 publications

References 12 publications

Pharmacologic properties of candesartan cilexetil—possible mechanisms of long-acting antihypertensive action

Pharmacologic properties of candesartan cilexetil—possible mechanisms of long-acting antihypertensive action

Determining the Potency and Molecular Mechanism of Action of Insurmountable Antagonists

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

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