Pharmacologic Analysis of Drug Receptor Interaction

Kenakin, Terrence Peter

doi:10.1097/00007691-198803000-00029

Cited by 457 publications

(498 citation statements)

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“…Since the curves were clearly shifted rightwards and downwards by compounds 4 or 10, it appears that neither drug could induce competitive receptor antagonism that would have required preservation of the agonist maximum response and parallel shift of the dose response curve to the right. Thus, while the inhibition evoked by AF-353 could be minimally reversed by the P2X3 agonist, the antagonism by compounds 4 or 10 was partially surmounted by the higher agonist concentrations, suggesting a complex mode of pharmacological block in which the non-competitive antagonism process was predominant, yet not exclusive [69]. Nonetheless, in the presence of a competitive antagonist, receptors are prone to fast desensitization (that is strongly dependent on agonist concentration) and therefore might unexpectedly exhibit an apparent noncompetitive antagonism when high agonist doses are used …”

Section: Biological Assaysmentioning

confidence: 94%

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Ben

Marchenkova

Thomas

et al. 2016

Purinergic Signalling

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Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABA A and 5-HT 3 receptors, whose membrane currents were unaffected by the tested compounds.

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Section: Biological Assaysmentioning

confidence: 94%

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Ben

Marchenkova

Thomas

et al. 2016

Purinergic Signalling

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“…Furthermore, different experimental conditions can also contribute to the discrepant findings. More generally, the extent to which the action of a competitive antagonist can be overcome by increasing the concentration of agonist is determined by the relative concentrations of two agents, by the association and dissociation rate constants for their binding, and by the duration of exposure of each (see Kenakin, 1997). The action of a competitive antagonist can therefore be surmountable under one set of experimental conditions and ionsurmountable under another.…”

Section: Sheykhzade Et Almentioning

confidence: 99%

“…An alternative explanation for the partially surmountable antagonism by BIBN4096BS is that the antagonist, when in close enough proximity to its binding site, may form a covalent bond with it, and the antagonist-receptor complex is then converted into a tight binding slow reversible state (irreversible competitive antagonist). This results in insurmountable antagonism in a system with little or no receptor reserve (see Kenakin, 1997).…”

Section: Sheykhzade Et Almentioning

confidence: 99%

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Sheykhzade

Lind

Edvinsson

2004

British J Pharmacology

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1 We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1- [(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. 2 BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. 3 At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the E max . 4 At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. 5 The efficacy and potency of CGRP was significantly greater in the smaller (lumen diameter B200 mm) human subcutaneous arteries compared to the larger ones. 6 The apparent agonist equilibrium dissociation constant, K A , for CGRP 1 receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. 7 Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP 1 -like receptor and the necessary component for the receptor activation. 8 In conclusion, the inhibitory action of BIBN4096BS at the low concentration (10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca 2 þ ] i ) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations (0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP 1 receptors in human subcutaneous arteries.

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“…The relatively high pK i values of the latter six compounds can be explained by the fact that, with respect to G protein-coupled receptors, pK i values of agonists are frequently particularly high when an agonist radioligand is used. The explanation for this phenomenon is that a ternary complex consisting of agonist radioligand, receptor and G protein is formed; under this experimental condition, the equilibrium dissociation constants are underestimated, i.e., relatively high a nities are obtained (Kenakin, 1993). Thus, not only the functional models examined in the present study but also the radioligand binding experiments with [ 3 H]-N a -methylhistamine suggest that some of the ligands including FUB 373 and FUB 407 exhibit agonistic e ects at H 3 receptors.…”

Section: British Journal Of Pharmacology Vol 132 (8)mentioning

confidence: 99%

Novel histamine H₃‐receptor antagonists and partial agonists with a non‐aminergic structure

Nickel

Bauer

Schlicker

et al. 2001

British J Pharmacology

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1 We determined the a nities of eight novel histamine H 3 -receptor ligands (ethers and carbamates) for H 3 -receptor binding sites and their agonistic/antagonistic e ects in two functional H 3 -receptor models. The compounds di er from histamine in that the ethylamine chain is replaced by a propyloxy chain; in the three ethers mentioned below (FUB 335, 373 and 407), R is n-pentyl, 3-methylbutyl and 3,3-dimethylbutyl, respectively. 2 The compounds monophasically inhibited [ 3 H]-N a -methylhistamine binding to mouse cerebral cortex membranes (pK i 7.51 ± 9.53). 3 The concentration-response curve of histamine for its inhibitory e ect on the electrically evoked [ 3 H]-noradrenaline over¯ow from mouse cortex slices was shifted to the right by these compounds (apparent pA 2 6.61 ± 8.00). Only FUB 373 and 407 inhibited the evoked over¯ow by themselves (intrinsic activities 0.3 and 0.4); these e ects were counteracted by the H 3 -receptor antagonist clobenpropit. 4 [ 35 S]-GTPgS binding to mouse cortex membranes was stimulated by the H 3 -receptor agonist (R)-a-methylhistamine in a manner sensitive to clobenpropit. Among the novel compounds only FUB 373 and 407 stimulated [ 35 S]-GTPgS binding (intrinsic activities 0.6 and 0.4). 5 In conclusion, the novel compounds are partial H 3 -receptor agonists (FUB 373 and 407) or H 3 -receptor antagonists; comparison with FUB 335 shows that the transition from antagonist to agonist is caused by a slight structural change. A protonated N atom in the side chain is not necessary for agonism at H 3 receptors, proposing a receptor-ligand interaction di erent from that of classical agonists.

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Pharmacologic Analysis of Drug Receptor Interaction

Cited by 457 publications

References 0 publications

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Novel histamine H₃‐receptor antagonists and partial agonists with a non‐aminergic structure

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Pharmacologic Analysis of Drug Receptor Interaction

Cited by 457 publications

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2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Novel histamine H3‐receptor antagonists and partial agonists with a non‐aminergic structure

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Novel histamine H₃‐receptor antagonists and partial agonists with a non‐aminergic structure