Tricyclic compounds as selective antimuscarinics. 2. Structure-activity relationships of M1-selective antimuscarinics related to pirenzepine

Eberlein, Wolfgang; Engel, Wolfhard; Trummlitz, Guenter; Schmidt, G; Hammer, Rudolf

doi:10.1021/jm00401a016

Cited by 29 publications

(26 citation statements)

References 6 publications

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“…The exocyclic amide group and the nitrogen atom in one of the two aromatic rings seem to have only a minor effect in terms of affinity and selectivity. 19 As such, we decided to conserve the essential 2-(4-methylpiperazin-1-yl)acetamide side chain in all of the novel derivatives, while the endocyclic amide group was replaced with an azo group and the central seven-membered ring was "opened" to generate a fully unconstrained photochromic unit. In addition, structural variations at this unit were rationally designed to obtain analogues endowed with different photochemical properties.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In particular, it inhibits the parasympathetic nervous system "rest-and-digest" response, reducing gastric acid secretion and muscle spasm. [17][18][19][20] Other potential applications have been considered, like slowing down myopia progression 21 and reducing the risk of lethal events in the ischemic heart disease. 22 The wide expression of M1 mAChRs in the hippocampus and medial prefrontal cortex suggests that M1-mediated signaling is important for cognitive and learning functions and plays a key role in several neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

“…Muscarinic receptors belong to the class A family of G-protein-coupled receptors (GPCRs) and are classified into five distinct subtypes. , The wide distribution of mAChRs in the body and the limited subtype selectivity of muscarinic drugs are the cause of their adverse effects, which have made these receptors an attractive target in photopharmacology. − Pirenzepine (Gastrozepine) is an M 1 -selective muscarinic antagonist marketed to treat peptic ulcers. In particular, it inhibits the parasympathetic nervous system “rest-and-digest” response, reducing gastric acid secretion and muscle spasm. − Other potential applications have been considered, like slowing down myopia progression and reducing the risk of lethal events in the ischemic heart disease . The wide expression of M 1 mAChRs in the hippocampus and medial prefrontal cortex suggests that M 1 -mediated signaling is important for cognitive and learning functions and plays a key role in several neurological disorders. , The development of photoswitchable M 1 ligands is thus of great interest for both therapeutic and research purposes.…”

Section: Introductionmentioning

confidence: 99%

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Rational Design of Photochromic Analogues of Tricyclic Drugs

et al. 2021

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Tricyclic chemical structures are the core of many important drugs targeting all neurotransmitter pathways. These medicines enable effective therapies to treat from peptic ulcer disease to psychiatric disorders. However, when administered systemically they cause serious adverse effects that limit their use. In order to obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimic the tricyclic chemical structure and display reversibly controlled activity. Pseudo analogs of the tricyclic antagonist pirenzepine demonstrate that this is an effective strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both in vitro and in cardiac atria ex vivo.Despite the applied chemical modifications to make pirenzepine derivatives sensitive to light stimuli, the most potent candidate of the set, cryptozepine-2, maintained a moderate but promising M1 vs M2 subtype selectivity. These photoswitchable "crypto-azologs" of tricyclic drugs might open a general way to spatiotemporally target their therapeutic action while reducing their systemic toxicity and adverse effects.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rational Design of Photochromic Analogues of Tricyclic Drugs

et al. 2021

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“…Also, a mAChR antagonist could be used as a pharmacological tool and aid in the development of selective mAChR antagonists, which in turn, may be useful for treatment of PD. Numerous small-molecule antagonists acting on mAChR 1 [114][115][116][117][118][119][120][121][122][123][124][125][126] and on mAChR 4 [127][128][129][130][131][132][133] have been identified.…”

Section: Muscarinic Receptorsmentioning

confidence: 99%

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

et al. 2017

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Parkinson's Disease (PD) is a long-term neurodegenative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated to long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated to dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused in a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure-and ligand-based in silico approaches for the development of small molecules to target these receptors.

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“…many years; AF-DX 116 (2) is the inhibitor of cardio (M 2 ) selective muscarinic receptor, which shows in vitro a 10-fold higher affinity for receptors of heart than for those of the cortex (M 1 ); [2][3][4] Nevirapine (3), the first non-nucleoside inhibitors of HIV-1 RT, is employed in the treatment of AIDS and AIDS-related complex (ARC) [5][6][7][8][9]. Moreover, as clozapine-like analogs, 8-chloro-6-(4 0 -methyl-l-piperazinyl)-11H-pyrido [2,3-b] [1,4] benzodiazepine (4) and 8-methyl-6-(4 0 -methyl-1-piperaziny1)-11H-pyrido [2,3-b] [1,4] benzodiazepine (5) showed the behavioral features for neuroleptics [10,11].…”

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confidence: 99%

A rapid synthetic method of pyridobenzodiazepines

et al. 2010

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A new one-pot Bischler-Napeiralski type cyclization reaction between pyridine-1,2-diamines and various carboxylic acids with PPA as catalyst to prepare pyridobenzodiazepines is proposed. In the new synthetic route, the reaction time is only one-third of the methods reported. The synthetic strategy provides an efficient way to prepare novel structurally diversified heterocyclic compounds of pyridobenzodiazepine family with potential pharmaceutical or biological activities.

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Tricyclic compounds as selective antimuscarinics. 2. Structure-activity relationships of M1-selective antimuscarinics related to pirenzepine

Cited by 29 publications

References 6 publications

Rational Design of Photochromic Analogues of Tricyclic Drugs

Rational Design of Photochromic Analogues of Tricyclic Drugs

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

A rapid synthetic method of pyridobenzodiazepines

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