Design, Synthesis, and Structure−Activity Relationship of Tropane Muscarinic Acetylcholine Receptor Antagonists

Abstract

Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.

Inhaled long-acting muscarinic antagonists in chronic obstructive pulmonary disease

“…Also, the epoxide moiety of tiotropium is also not present. Darotropium is a potent muscarinic antagonist, which exhibited pA 2 values of 11.4, 10.3 and 10.7 at the M 1 , M 2 and M 3 mAChRs, respectively [57]. In an in vivo mouse model, the compound inhibited methacholine-induced bronchoconstriction when dosed at 5 µg per mouse.…”

“…In an in vivo mouse model, the compound inhibited methacholine-induced bronchoconstriction when dosed at 5 µg per mouse. The presence of a quaternary salt on the template has an effect on the pharmacokinetic properties of darotropium, which are characterized by low absorption, high plasma clearance and low oral bioavailability [57], all of which are desirable characteristics for an inhaled drug candidate. No clinical data have yet been published.…”

Acid-catalyzed reaction of 1-(2,2-dimethoxyethyl)ureas with phenols as an effective approach to diarylethanes and dibenzoxanthenes

“…Diarylethanes containing urea fragments are known for their pharmacological activity. According to the literature, these compounds exhibit antibacterial activity, [1][2][3] may act as inhibitors of lysine-specific histone demethylase 1 (LSD1) 4 and antagonists of muscarinic acetylcholine 5 and chemokine type 3 receptors (CCR3) 6 . Additionally, some of them can be used in malaria 7 and sclerosis 8 treatment (Figure 1, A).…”

Bronchodilating Drugs for Chronic Obstructive Pulmonary Disease: Current Status and Future Trends

“…22 Searching for novel inhaled LAMA, Lainéet al identified a new series of N-substituted tropane derivatives which were characterized as potent M 3 mAcChR antagonists. 39 SARs at the M 3 mAcChR of a N-substituted series of analogs of compound 1 (darotropium) (Figure 9B) have been studied. 39 Quaternary salts 3−15 derived from darotropium were obtained as a mixture of two isomers.…”

“…39 SARs at the M 3 mAcChR of a N-substituted series of analogs of compound 1 (darotropium) (Figure 9B) have been studied. 39 Quaternary salts 3−15 derived from darotropium were obtained as a mixture of two isomers. 39 The N-endo derivatives possessing the pending chain on the same side as the C-3 substituent were more potent than N-exo isomers having the chain on the opposite side as the C-3 substituent.…”