Novel long‐acting antagonists of muscarinic ACh receptors

Abstract

Background and PurposeThe aim of this study was to develop potent and long‐acting antagonists of muscarinic ACh receptors. The 4‐hexyloxy and 4‐butyloxy derivatives of 1‐[2‐(4‐oxidobenzoyloxy)ethyl]‐1,2,3,6‐tetrahydropyridin‐1‐ium were synthesized and tested for biological activity. Antagonists with long‐residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long‐acting effects allow for reduced daily doses and adverse effects.Experimental ApproachThe binding and antagonism of functional responses to the agonist carbachol mediated by 4‐hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4‐butyloxy analogues.Key ResultsThe 4‐hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M1 to 4 μM at M3 receptors. Under washing conditions to reverse antagonism, the half‐life of their antagonistic action ranged from 1.7 h at M2 to 5 h at M5 receptors.Conclusions and ImplicationsThe 4‐hexyloxy derivatives were found to be potent long‐acting M1‐preferring antagonists. In view of current literature, M1‐selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits.

Cyclic Stretch Promotes Proliferation and Contraction of Human Bladder Smooth Muscle Cells by Cajal-Mediated c-kit Expression in Interstitial Cells

“…The bladder detrusor muscle simultaneously expresses M2 and M3 subtypes of M receptors, but M3 is the only one directly related to detrusor contraction [15,16]. M2 synergizes with beta receptors to inhibit detrusor relaxation and assist in urination under the action of large doses of Ach [17,18].…”

Cell-Based Reporter Release Assay to Determine the Activity of Calcium-Dependent Neurotoxins and Neuroactive Pharmaceuticals

“…Development of new selective and potent muscarinic acetylcholine receptor antagonists either by de novo synthesis or screening of animal venoms is of note in the treatment of neuronal diseases [ 26 ]. Screening for anti-cholinergic drugs includes the structure guided development of M3 receptor specific antagonists [ 27 ] and the identification of M1 vs. M3 receptor selective drugs [ 28 ]. New antagonists were analyzed either by radioligand-binding studies with the membrane of M1-5 receptor transfected CHO cells or by functional studies (IP-formation and ß-arrestin recruitment) with receptor-overexpressing CHO and HEK293 cells.…”

Urinary Incontinence – from Childhood Onwards

“…Most antimuscarinics have a similar side effect profile, which includes dryness of the mouth and eyes, and constipation. Second- and third-generation selective antimuscarinics have relatively more affinity for M2 and M3 receptors, which are most prevalent in the bladder, reducing side effects in other systems ( 35 ).…”