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1.
ACS Chem Neurosci ; 9(9): 2218-2224, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-29683646

RESUMO

Positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M1 PAMs may reduce efficacy and contribute to adverse effect liability. However, the M1 PAM PF-06827443 was reported to have only weak agonist activity at human M1 receptors but produced M1-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M1 and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.


Assuntos
Isoindóis/farmacologia , Oxazóis/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptor Muscarínico M1/agonistas , Convulsões/induzido quimicamente , Convulsões/metabolismo , Regulação Alostérica , Animais , Células CHO , Cálcio/metabolismo , Cricetulus , Cães , Humanos , Camundongos , Técnicas de Patch-Clamp , Córtex Pré-Frontal/metabolismo , Ratos
2.
ACS Chem Neurosci ; 9(9): 2274-2285, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-29701957

RESUMO

Selective activation of the M1 subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M1 ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M1 PAM, VU0486846. VU0486846 possesses only weak agonist activity in M1-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [3H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M1 PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M1 PAM activity (EC50 > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M1. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.


Assuntos
Cognição/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Morfolinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Pirazóis/farmacologia , Regulação Alostérica , Animais , Antipsicóticos/toxicidade , Células CHO , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Cricetulus , Medo , Camundongos , Morfolinas/toxicidade , Pirazóis/toxicidade , Ratos , Risperidona/toxicidade , Convulsões/induzido quimicamente
3.
Neuropsychopharmacology ; 43(8): 1763-1771, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29581537

RESUMO

Highly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer's disease and schizophrenia. However, excessive activation of M1 is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M1 PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M1 receptor and disrupt PFC function. In contrast, structurally distinct M1 PAMs (VU0453595 and VU0550164) are devoid of agonist activity in cell lines and maintain activity dependence of M1 activation in the PFC. Consistent with the previously reported effect of PF-06764427, the ago-PAM MK-7622 induces severe behavioral convulsions in mice. In contrast, VU0453595 does not induce behavioral convulsions at doses well above those required for maximal efficacy in enhancing cognitive function. Furthermore, in contrast to the robust efficacy of VU0453595, the ago-PAM MK-7622 failed to improve novel object recognition, a rodent assay of cognitive function. These findings suggest that in vivo cognition-enhancing efficacy of M1 PAMs can be observed with PAMs lacking intrinsic agonist activity and that intrinsic agonist activity of M1 PAMs may contribute to adverse effects and reduced efficacy in improving cognitive function.


Assuntos
Colinérgicos/farmacologia , Nootrópicos/farmacologia , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Animais , Células CHO , Cricetulus , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/genética , Reconhecimento Psicológico/efeitos dos fármacos , Técnicas de Cultura de Tecidos
4.
ACS Med Chem Lett ; 8(12): 1326-1330, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29259756

RESUMO

Herein, we report the structure-activity relationships within a series of mGlu7 NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (Kp 1.9-5.8 and Kp,uu 0.4-1.4). Analogues in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiology studies.

5.
Neuron ; 96(6): 1358-1372.e4, 2017 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-29268098

RESUMO

Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M4) to oppose cAMP-dependent dopamine receptor subtype 1 (D1) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D1-mediated activation of motor activity. These studies provide important new insights into the unique role of M4 in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output.


Assuntos
Gânglios da Base/citologia , Neurônios Colinérgicos/fisiologia , Dopamina/metabolismo , Parte Reticular da Substância Negra/fisiologia , Receptor Muscarínico M4/metabolismo , Acetilcolina/metabolismo , Animais , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/fisiologia , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Colina O-Acetiltransferase/metabolismo , Colinérgicos/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Dopamina/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/genética , Locomoção/efeitos dos fármacos , Locomoção/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurotransmissores/farmacologia , Oxigênio/sangue , Parte Reticular da Substância Negra/citologia , Parte Reticular da Substância Negra/diagnóstico por imagem , Núcleo Tegmental Pedunculopontino/citologia , Receptor Muscarínico M4/genética , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
ACS Chem Neurosci ; 8(4): 866-883, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28001356

RESUMO

Both historical clinical and recent preclinical data suggest that the M1 muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M1 activation. Efforts then shifted to focus on selective activation of M1 via either allosteric agonists or positive allosteric modulators (PAMs). While M1 PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M1 ago-PAMs. Our data demonstrate that closely related M1 PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M1 PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M1 responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M1 PAMs.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Descoberta de Drogas , Agonistas Muscarínicos/química , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/efeitos dos fármacos , Animais , Humanos , Camundongos , Agonistas Muscarínicos/síntese química , Ratos , Receptor Muscarínico M1/metabolismo , Relação Estrutura-Atividade
7.
Neuron ; 91(6): 1244-1252, 2016 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-27618677

RESUMO

Muscarinic receptors represent a promising therapeutic target for schizophrenia, but the mechanisms underlying the antipsychotic efficacy of muscarinic modulators are not well understood. Here, we report that activation of M4 receptors on striatal spiny projection neurons results in a novel form of dopaminergic regulation resulting in a sustained depression of striatal dopamine release that is observed more than 30 min after removal of the muscarinic receptor agonist. Furthermore, both the M4-mediated sustained inhibition of dopamine release and the antipsychotic-like efficacy of M4 activators were found to require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism by which striatal cholinergic and cannabinoid signaling leads to sustained reductions in dopaminergic transmission and concurrent behavioral effects predictive of antipsychotic efficacy.


Assuntos
Antipsicóticos/farmacologia , Dopamina/metabolismo , Agonistas Muscarínicos/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Receptor Muscarínico M4/fisiologia , Regulação Alostérica/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Lipase Lipoproteica/antagonistas & inibidores , Camundongos Knockout , Oxotremorina/análogos & derivados , Oxotremorina/farmacologia , Inibição Pré-Pulso/efeitos dos fármacos , Piridazinas/farmacologia , Receptor CB2 de Canabinoide/fisiologia , Receptor Muscarínico M4/agonistas , Tiofenos/farmacologia
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