A novel m2-selective muscarinic antagonist: binding characteristics and autoradiographic distribution in rat brain

Gitler, Miriam S.; Reba, Richard C.; Cohen, Victor Israel; Rzeszotarski, W. J.; Baumgold, Jesse

doi:10.1016/0006-8993(92)90141-u

Cited by 34 publications

(20 citation statements)

References 28 publications

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“…The greater effectiveness we found of the m1R-over m2R-class cholinergic blockers, as well as the positive result with the m1R agonist McN-A-343, suggests that ADPs were recruited through actions on m1 (or m3/m5) receptors. The weak blockade of ADPs by AFDX-116 is consistent with the moderate (125-750 nM) (Gitler et al 1992;Billard et al 1995;Mansfield et al 2003) affinity of this m2-selective agent for m1-class receptors. Our results also are consistent with ultrastructural work (Deller et al 1999) demonstrating that choline acetyltransferase (ChAT)-positive boutons contact mossy cell somata and proximal dendrites.…”

Section: Discussionsupporting

confidence: 53%

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Regulation of persistent activity in hippocampal mossy cells by inhibitory synaptic potentials

Anderson

Strowbridge

2014

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The hippocampal formation receives strong cholinergic input from the septal/diagonal band complex. Although the functional effects of cholinergic activation have been extensively studied in pyramidal neurons within the hippocampus and entorhinal cortex, less is known about the role of cholinergic receptors on dentate gyrus neurons. Using intracellular recordings from rat dentate hilar neurons, we find that activation of m1-type muscarinic receptors selectively increases the excitability of glutamatergic mossy cells but not of hilar interneurons. Following brief stimuli, cholinergic modulation reveals a latent afterdepolarization response in mossy cells that can extend the duration of stimulus-evoked depolarization by .100 msec. Depolarizing stimuli also could trigger persistent firing in mossy cells exposed to carbachol or an m1 receptor agonist. Evoked IPSPs attenuated the ADP response in mossy cells. The functional effect of IPSPs was amplified during ADP responses triggered in the presence of cholinergic receptor agonists but not during slowly decaying simulated ADPs, suggesting that modulation of ADP responses by IPSPs arises from destabilization of the intrinsic currents underlying the ADP. Evoked IPSPs also could halt persistent firing triggered by depolarizing stimuli. These results show that through intrinsic properties modulated by muscarinic receptors, mossy cells can prolong depolarizing responses to excitatory input and extend the time window where multiple synaptic inputs can summate. By actively regulating the intrinsic response to synaptic input, inhibitory synaptic input can dynamically control the integration window that enables detection of coincident inputs and shape the spatial pattern of hilar cell activity.Both the dentate gyrus and the hippocampus receive robust cholinergic input from the septum/diagonal band complex (Frotscher et al. 1992;Lübke et al. 1997;Deller et al. 1999). Although previous investigators have examined the functional effect of cholinergic modulation in hippocampal neurons (Halliwell 1990), less is known about the consequences of cholinergic stimulation on dentate gyrus neurons, including hilar neurons, a primary target of cholinergic afferents (Amaral 1978;Frotscher et al. 1992). The dentate hilus contains both excitatory mossy cells (MCs) that project axons large distances ipsilaterally and contralaterally along the septotemporal axis of the hippocampal formation, as well as GABAergic interneurons (Scharfman and Schwartzkroin 1988;Buckmaster et al. 1996;Larimer and Strowbridge 2008). Mossy cells predominately excite granule cells outside of the local region of the dentate gyrus where their soma and dendritic arbor reside (Buckmaster et al. 1996), enabling them to transmit information broadly throughout the hippocampal formation. Periodic discharges in dentate gyrus neurons at theta-band frequencies often are affected by experimental manipulations of cholinergic receptors or projection neurons, though the specific cellular pathways that mediate cholinergic oscillations...

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Section: Discussionsupporting

confidence: 53%

“…2A). By contrast, the m2-class receptor antagonist AF-DX 116 (1 mM) (Gitler et al 1992) had only small effects on step-evoked ADP responses in the same concentration of CCh (29.3% reduction) (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

Regulation of persistent activity in hippocampal mossy cells by inhibitory synaptic potentials

Anderson

Strowbridge

2014

Learn. Mem.

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“…Linking orthosteric ( 1 , 3 , and 4 ) and allosteric ( 11 and 12 ) MR ligands with a M 2 R preferring dibenzodiazepinone-type MR antagonist ( 8 ) yielded a series of heterodimeric ligands ( 34 , 38 , 39 , 43 , 44 , 46 , 48 , 50–52 , 60 , 61 , 63 , 64 , 66 , 67 , 69 , 70 , and 72 ). The “ 8–1 ” type dimeric ligand 46 (UR-SK75), containing a piperazine moiety in the linker, exhibited a higher M 2 R affinity (p K i 10.14) and selectivity [expressed as the ratio of K i values (M 1 /M 2 /M 3 /M 4 /M 5 ): 23:1:180:29:430] compared to monomeric (such as 8 ( 46 ) and 10 ( 22 , 23 )) and homodimeric (e.g., 18 ( 22 ) and 19 ( 23 )) dibenzodiazepinone-type ligands. High M 2 R affinity of all dibenzodiazepinone-type heterodimeric ligands (p K i > 8.3, Table 1 ), as also reported for monomeric dibenzodiazepinone-type ligands, 22 suggested a minor influence of the second pharmacophore on M 2 R binding, indicating that the high M 2 R affinity of these compounds is mediated by the “dibenzodiazepinone” pharmacophore, which binds most likely to the orthosteric binding site of the M 2 R. This is supported by the proposed binding mode of 10 and 19 at the M 2 R, 23 by saturation-binding studies using the radioligands [ 3 H] 44 ([ 3 H]UR-SK71) and [ 3 H] 64 ([ 3 H]UR-SK59), and by the fact that compounds containing M 1 R/M 4 R selective agonist 1 ( 49 ) as a second pharmacophore ( 43 , 44 , 46 , 60 , and 61 ) proved to be M 2 R-preferring ligands.…”

Section: Discussionmentioning

confidence: 99%

Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M₂R Affinity and Selectivity

et al. 2017

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In search for selective ligands for the muscarinic acetylcholine receptor (MR) subtype M2, the dimeric ligand approach, that is combining two pharmacophores in one and the same molecule, was pursued. Different types (agonists, antagonists, orthosteric, and allosteric) of monomeric MR ligands were combined by various linkers with a dibenzodiazepinone-type MR antagonist, affording five types of heterodimeric compounds (“DIBA-xanomeline,” “DIBA-TBPB,” “DIBA-77-LH-28-1,” “DIBA-propantheline,” and “DIBA-4-DAMP”), which showed high M2R affinities (pKi > 8.3). The heterodimeric ligand UR-SK75 (46) exhibited the highest M2R affinity and selectivity [pKi (M1R–M5R): 8.84, 10.14, 7.88, 8.59, and 7.47]. Two tritium-labeled dimeric derivatives (“DIBA-xanomeline”-type: [3H]UR-SK71 ([3H]44) and “DIBA-TBPB”-type: [3H]UR-SK59 ([3H]64)) were prepared to investigate their binding modes at hM2R. Saturation-binding experiments showed that these compounds address the orthosteric binding site of the M2R. The investigation of the effect of various allosteric MR modulators [gallamine (13), W84 (14), and LY2119620 (15)] on the equilibrium (13–15) or saturation (14) binding of [3H]64 suggested a competitive mechanism between [3H]64 and the investigated allosteric ligands, and consequently a dualsteric binding mode of 64 at the M2R.

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“…37 30,[32][33][34][35][36] (in case of 1 30 and 2, 33 . 38,39 Prompted by the recently reported synthesis and characterization of radiolabeled dualsteric M 2 R antagonists derived from the M 2 R preferring dibenzodiazepinone DIBA (5) 40 (for instance,…”

Section: Introductionmentioning

confidence: 99%

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor

et al. 2020

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Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M R affinities (pK i (radioligand competition binding): 9.10-9.59). Binding studies at M 1 and M 3 -M 5 receptors indicated a M 2 R preference. Flow cytometric and high-content imaging saturation and competition binding (M 1 R, M 2 R and M 4 R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM 2 R cells). Results from dissociation and saturation binding experiments (M 2 R) in the presence of allosteric M 2 R modulators (dissociation: W84, LY2119620 and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M 2 R in imaging and binding studies, and suggest that they have a dualsteric mode of action.

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A novel m2-selective muscarinic antagonist: binding characteristics and autoradiographic distribution in rat brain

Cited by 34 publications

References 28 publications

Regulation of persistent activity in hippocampal mossy cells by inhibitory synaptic potentials

Regulation of persistent activity in hippocampal mossy cells by inhibitory synaptic potentials

Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M₂R Affinity and Selectivity

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor

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A novel m2-selective muscarinic antagonist: binding characteristics and autoradiographic distribution in rat brain

Cited by 34 publications

References 28 publications

Regulation of persistent activity in hippocampal mossy cells by inhibitory synaptic potentials

Regulation of persistent activity in hippocampal mossy cells by inhibitory synaptic potentials

Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M2R Affinity and Selectivity

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor

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Product

Resources

About

Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M₂R Affinity and Selectivity

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor