Convergent, short synthesis of the muscarinic superagonist iperoxo

Kloeckner, Jessica; Schmitz, Jens; Holzgrabe, Ulrike

doi:10.1016/j.tetlet.2010.04.130

Cited by 27 publications

(28 citation statements)

References 10 publications

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“…Iperoxo (( 1 ) in Fig. 1b), the orthosteric building block of the dualsteric compounds, is a super-potent muscarinic agonist characterized by an affinity-enhancing Δ 2 -isoxazoline ring system and was re-synthesized as previously described28. Iperoxo is 100-fold more potent than ACh as reported below and was chosen as the orthosteric building block of the dualsteric probes to ensure high-fidelity receptor activation via the orthosteric-binding site.…”

Section: Resultsmentioning

confidence: 99%

The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

et al. 2012

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Seven transmembrane helical receptors (7TMRs) modulate cell function via different types of G proteins, often in a ligand-specific manner. Class A 7TMRs harbour allosteric vestibules in the entrance of their ligand-binding cavities, which are in the focus of current drug discovery. However, their biological function remains enigmatic. Here we present a new strategy for probing and manipulating conformational transitions in the allosteric vestibule of label-free 7TMRs using the M2 acetylcholine receptor as a paradigm. We designed dualsteric agonists as 'tailor-made' chemical probes to trigger graded receptor activation from the acetylcholine-binding site while simultaneously restricting spatial flexibility of the receptor's allosteric vestibule. Our findings reveal for the first time that a 7TMR's allosteric vestibule controls the extent of receptor movement to govern a hierarchical order of G-protein coupling. This is a new concept assigning a biological role to the allosteric vestibule for controlling fidelity of 7TMR signalling.

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Section: Resultsmentioning

confidence: 99%

The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

et al. 2012

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“…Synthesis of M 1 Orthosteric Agonist Compound 1 a a Reagents and conditions: (i) NaNO 2 (1.2 equiv), KBr (3 equiv), HBr (47% soln), water, 0°C to rt, 62%; (ii) (1) KOH (0.95 equiv), potassium ethyl xanthate (1.1 equiv), water, 50°C, 2 h, (2) diethylenediamine dihydrochloride (2 equiv), KOH soln (4 equiv), 50°C, 2 h, 61%; (iii) 1-Boc-4-piperidinone (0.7 equiv), (NH 4 ) 2 CO 3 (1 equiv), benzene, reflux, 48 h, 63%; (iv) HCl (5 M alcohol of the corresponding spacer length (C4 and C6) and the hydroxyl function (11,12) substituted by a bromine atom using HBr/H 2 SO 4 . Finally, iperoxo, synthesized according to a method previously described, 45 was connected to the spacer (Scheme 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

et al. 2014

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Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy.

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“…3). 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.…”

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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Convergent, short synthesis of the muscarinic superagonist iperoxo

Cited by 27 publications

References 10 publications

The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

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

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Convergent, short synthesis of the muscarinic superagonist iperoxo

Cited by 27 publications

References 10 publications

The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

Rational Design of Partial Agonists for the Muscarinic M1 Acetylcholine Receptor

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

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Product

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Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

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