Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M
Università degli studi di Parma, Parma, Emilia-Romagna, Italy Bioorganic & Medicinal Chemistry
(Impact Factor: 2.79).
09/1999; 7(8):1539-47. DOI: 10.1016/S0968-0896(99)00107-8
Two subseries of nonquaternized (5a-10a) and quaternized derivatives (5b-10b) related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compounds was estimated in three classical in vitro functional assays: M1 rabbit vas deferens, M2 guinea pig left atrium and M3 guinea pig ileum. In addition, the occurrence of central muscarinic effects was evaluated as tremorigenic activity after intraperitoneal administration in mice. In in vitro tests a nonselective muscarinic activity was exhibited by all the derivatives with potencies values that, in some instances, surpassed those of the reference compounds (i.e. 8b). Functional selectivity was evidenced only for the oxotremorine-like derivative 9a, which behaved as a mixed M3-agonist/M1-antagonist (pD2 = 5.85; pA2 = 4.76, respectively). In in vivo tests non-quaternary compounds were able to evoke central muscarinic effects, with a potency order parallel to that observed in vitro.
Available from: Hongling Xiao
- "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. 2A), and then expanded the pharmacological characterization to the M 4 receptor subtype and found similar nanomolar potency (EC 50 5 8.47 6 3.00 nM, and 61-fold enhancement in the EC 50(Ach) /EC 50(Iperoxo) ; Fig. 2B). "
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ABSTRACT: The M4 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 anti-psychotic and pro-cognitive efficacy. Recent efforts have shifted toward allosteric ligands to maximize receptor selectivity and manipulate endogenous cholinergic and dopaminergic signaling. Here we present the pharmacological characterization of LY2119620, an M2/M4 receptor selective positive-allosteric modulator (PAM), chemically evolved from hits identified through an M4-allosteric functional screen. Though unsuitable as a therapeutic due to M2 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 radio-tracer. Characterization of LY2119620 revealed evidence of probe-dependence in both binding and functional assays. GTP-γ-S assays displayed differential potentiation depending on the orthosteric-allosteric pairing with the largest cooperativity observed for Oxo-M-LY2119620. Further [(3)H]-Oxo-M saturation binding, including studies with GppNHp, suggest 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 M4 receptor, and demonstrates that an allosteric ligand can positively modulate the binding and functional efficacy of this high efficacy ligand. Ultimately it was the M2 receptor pharmacology and PAM activity with iperoxo which made LY2119620 the most suitable allosteric partner for the M2 active-state structure recently solved (Kruse et al. 2013); a structure which provides crucial insights into the mechanisms of orthosteric activation and allosteric modulation of muscarinic receptors.
Available from: Evi Kostenis
- "Efficacy is indicated by dot colour – green: agonist activity, red: antagonist activity. Values for a–d are taken from Dallanoce et al. (1999), for W84 from Tränkle et al., 1998, for 1a–1c from Disingrini et al. (2006) and for 1d from Antony et al. (2009). "
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ABSTRACT: Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCR-complexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine-tuned GPCR-modulation.
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ABSTRACT: Two subsets of tertiary amines (1a-6a) and methiodides (1b-6b) with a structural resemblance to oxotremorine and oxotremorine-M were tested at rabbit vas deferens (M1), guinea pig left atrium (M2), guinea pig ileum and urinary bladder (M3) muscarinic receptor subtypes. The pharmacological profile of the derivatives under study has been discussed by evaluating their potency, affinity and efficacy as well as the regional differences in muscarinic receptor occupancy.
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