Allosteric Modulation

Kenakin, Terry

doi:10.1016/b978-0-12-813957-8.00007-2

Cited by 2 publications

(2 citation statements)

References 54 publications

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“…The equilibrium dissociation constant of antagonism of functional response K B was calculated from the shift in EC 50 of functional response to carbachol by antagonist according to Schild equation for a competitive antagonist, Equation , or an allosteric antagonist, Equation (Kenakin, ).

log ((), italicDR - 1) = log ((), [B]) - log ((), K_{B}),

where DR is the ratio of EC 50 of the functional response in the presence to the absence of antagonist B.…”

Section: Methodsmentioning

confidence: 99%

Novel long‐acting antagonists of muscarinic ACh receptors

Randáková

Rudajev

Doležal

et al. 2018

British J Pharmacology

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Background and PurposeThe aim of this study was to develop potent and long‐acting antagonists of muscarinic ACh receptors. The 4‐hexyloxy and 4‐butyloxy derivatives of 1‐[2‐(4‐oxidobenzoyloxy)ethyl]‐1,2,3,6‐tetrahydropyridin‐1‐ium were synthesized and tested for biological activity. Antagonists with long‐residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long‐acting effects allow for reduced daily doses and adverse effects.Experimental ApproachThe binding and antagonism of functional responses to the agonist carbachol mediated by 4‐hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4‐butyloxy analogues.Key ResultsThe 4‐hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M1 to 4 μM at M3 receptors. Under washing conditions to reverse antagonism, the half‐life of their antagonistic action ranged from 1.7 h at M2 to 5 h at M5 receptors.Conclusions and ImplicationsThe 4‐hexyloxy derivatives were found to be potent long‐acting M1‐preferring antagonists. In view of current literature, M1‐selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits.

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log ((), italicDR - 1) = log ((), [B]) - log ((), K_{B}),

where DR is the ratio of EC 50 of the functional response in the presence to the absence of antagonist B.…”

Section: Methodsmentioning

confidence: 99%

Novel long‐acting antagonists of muscarinic ACh receptors

Randáková

Rudajev

Doležal

et al. 2018

British J Pharmacology

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“…Studies have shown that targeting the heterodimeric gamma-aminobutyric acid B (GABA B ) receptor, using positive allosteric modulators (PAMs) that can bind at the interface of the transmembrane domains, can control the activation of this class C GPCR dimer ( 97 ). PAMs are allosteric modulators that enhance the agonist affinity for the receptor and negative allosteric modulators (NAMs) will inhibit the agonist affinity ( 98 ). The GABA B PAMs bind in the transmembrane interface which is conserved across most GPCRs, making these findings important for not only class C GPCRs, but for the whole superfamily ( 97 ).…”

Section: Introductionmentioning

confidence: 99%

Probing GPCR Dimerization Using Peptides

2022

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G protein-coupled receptors (GPCRs) are the largest class of membrane proteins and the most common and extensively studied pharmacological target. Numerous studies over the last decade have confirmed that GPCRs do not only exist and function in their monomeric form but in fact, have the ability to form dimers or higher order oligomers with other GPCRs, as well as other classes of receptors. GPCR oligomers have become increasingly attractive to investigate as they have the ability to modulate the pharmacological responses of the receptors which in turn, could have important functional roles in diseases, such as cancer and several neurological & neuropsychiatric disorders. Despite the growing evidence in the field of GPCR oligomerisation, the lack of structural information, as well as targeting the ‘undruggable’ protein-protein interactions (PPIs) involved in these complexes, has presented difficulties. Outside the field of GPCRs, targeting PPIs has been widely studied, with a variety of techniques being investigated; from small-molecule inhibitors to disrupting peptides. In this review, we will demonstrate several physiologically relevant GPCR dimers and discuss an array of strategies and techniques that can be employed when targeting these complexes, as well as provide ideas for future development.

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Allosteric Modulation

Cited by 2 publications

References 54 publications

Novel long‐acting antagonists of muscarinic ACh receptors

Novel long‐acting antagonists of muscarinic ACh receptors

Probing GPCR Dimerization Using Peptides

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