Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M

Dallanoce, Clelia; Conti, Paola; Amici, Marco De; Micheli, Carlo De; Barocelli, Elisabetta; Chiavarini, M.; Ballabeni, Vigilio; Bertoni, Simona; Impicciatore, M

doi:10.1016/s0968-0896(99)00107-8

Cited by 41 publications

(40 citation statements)

References 25 publications

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“…Another important result of this study was the characterization of the potent agonist, iperoxo, to date described in the literature as a M 2 superagonist (Kloeckner et al, 2010;Bock et al, 2012;Schrage et al, 2013), and its modulation by an allosteric ligand. Originating from screens for novel derivatives of Oxo-M (Dallanoce et al, 1999), iperoxo was found to possess both superior affinity and efficacy over ACh. Our work recapitulated previous findings that iperoxo possessed an EC 50 of 2.12 6 0.0953 nM at the M 2 receptor (EC 50(Ach) /EC 50(Iperoxo) 5 56-fold; Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M₂and M₄Receptors

et al. 2014

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The M 4 receptor is a compelling therapeutic target, as this receptor modulates neural circuits dysregulated in schizophrenia, and there is clinical evidence that muscarinic agonists possess both antipsychotic and procognitive efficacy. Recent efforts have shifted toward allosteric ligands to maximize receptor selectivity and manipulate endogenous cholinergic and dopaminergic signaling. In this study, we present the pharmacological characterization of LY2119620receptor-selective positive allosteric modulator (PAM), chemically evolved from hits identified through a M 4 allosteric functional screen. Although unsuitable as a therapeutic due to M 2 receptor cross-reactivity and, thus, potential cardiovascular liability, LY2119620 surpassed previous congeners in potency and PAM activity and broadens research capabilities through its development into a radiotracer. Characterization of LY2119620 revealed evidence of probe dependence in both binding and functional assays. Guanosine 59-[g- triphosphate, suggests that both the orthosteric and allosteric ligands can alter the population of receptors in the active G protein-coupled state. Additionally, this work expands the characterization of the orthosteric agonist, iperoxo, at the M 4 receptor, and demonstrates that an allosteric ligand can positively modulate the binding and functional efficacy of this high efficacy ligand. Ultimately, it was the M 2 receptor pharmacology and PAM activity with iperoxo that made LY2119620 the most suitable allosteric partner for the M 2 active-state structure recently solved (Kruse et al., 2013), a structure that provides crucial insights into the mechanisms of orthosteric activation and allosteric modulation of muscarinic receptors.

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Section: Discussionmentioning

confidence: 99%

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M₂and M₄Receptors

et al. 2014

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“…The quaternary head group is essential for the receptor interaction of ACh and related conventional agonists (Lu et al, 2002). When one of the methyl residues of the head group in iperoxo is replaced by a hydrogen (yielding 'IP-H', Figure 1), potency declines in isolated tissue preparations by about 1-2 log units (Dallanoce et al, 1999). In order to further clarify the role of the head group for the signalling of iperoxo, we enlarged the head group by replacing a methyl substituent by either n-propyl or n-pentyl, yielding 'IP-C3' and 'IP-C5' respectively ( Figure 1).…”

Section: Targeted Modifications Of Iperoxo Serve To Understand Structmentioning

confidence: 99%

“…Iperoxo is a muscarinic ACh receptor agonist with outstanding potency (Dallanoce et al, 1999). The compound has recently gained increasing interest as an essential building block for a novel class of GPCR modulators (Antony et al, 2009;Mohr et al, 2010;Valant et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Agonists with supraphysiological efficacy at the muscarinic M₂ ACh receptor

Schrage

Seemann

Klöckner

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEArtificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such 'superagonism' has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a 'superagonist'. EXPERIMENTAL APPROACHSignalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. KEY RESULTSIn CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi/Gs signalling competence. In the orthosteric loss-of-function mutant M2-Y104 3.33 A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. 'Superagonism' is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure-signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that 'superagonism' of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. CONCLUSION AND IMPLICATIONSSupraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR 'superagonism' is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators.

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“…Since M 1 and M 3 receptors use the same intracellular signaling pathway, the activation of all of these receptors might not be needed to produce a full response. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 ACh and OxoM are known to be non-selective full muscarinic agonists (Dallanoce et al, 1999). In the presents study, these two agonists induced inward currents with similar affinity and potency.…”

Section: Subtype Of Muscarinic Receptormentioning

confidence: 99%

Muscarinic receptor-mediated excitation of rat intracardiac ganglion neurons

et al. 2015

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Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M

Cited by 41 publications

References 25 publications

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M₂and M₄Receptors

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M₂and M₄Receptors

Agonists with supraphysiological efficacy at the muscarinic M₂ ACh receptor

Muscarinic receptor-mediated excitation of rat intracardiac ganglion neurons

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Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M

Cited by 41 publications

References 25 publications

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M2and M4Receptors

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M2and M4Receptors

Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor

Muscarinic receptor-mediated excitation of rat intracardiac ganglion neurons

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Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M₂and M₄Receptors

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M₂and M₄Receptors

Agonists with supraphysiological efficacy at the muscarinic M₂ ACh receptor