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Structure‐activity relationships of new analogues of arecaidine propargyl ester at muscarinic M 1 and M 2 receptor subtypes
Author(s) -
Moser U.,
Lambrecht G.,
Wagner M.,
Wess J.,
Mutschler E.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb11820.x
Subject(s) - agonist , muscarinic acetylcholine receptor , receptor , ileum , potency , stereochemistry , chemistry , ec50 , biochemistry , in vitro
1 The potency of arecaidine propargyl ester (APE) and of several analogues containing a modified ester side chain has been assessed at M 1 and M 2 muscarinic receptor subtypes. APE was shown to act as a potent agonist at ganglionic M 1 receptors in the pithed rat, at M 2 receptors in guinea‐pig isolated atria (‐log EC 50 = 8.22) and ileum (‐log EC 50 = 7.77). 2 The arecaidine 2‐butynyl and 2‐pentynyl esters were approximately equipotent with APE at M 1 and M 2 receptors, whereas the 2‐hexynyl derivative was found to be less potent than APE in atria (‐log EC 50 = 6.80) and ileum (‐log EC 50 = 6.70) by about one order of magnitude. The 2‐heptynyl and 3‐phenyl propargyl esters exhibited no agonist actions in atria and ileum. 3 Shifting the triple bond from the 2 to the 3 position and introducing a bulky group at position 1 of the ester side chain of APE and analogues resulted in competitive antagonists (pA 2 ranging from 4.9 to 7.3). 4 APE and its 2‐butynyl analogue showed some agonistic selectivity for cardiac M 2 receptors (potency ratio, ileum/atria = 2.8 and 4.6 respectively). All antagonists in this series of compounds were not selective in terms of affinity since their pA 2 values at cardiac and ileal M 2 receptors were similar (potency ratios, ileum/atria = 0.4 to 1.2).