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Pharmacological in vitro characterization of the arecoline bioisostere, Lu 25‐109‐T, a muscarinic compound with M 1 ‐agonistic and M 2 /M 3 ‐antagonistic properties
Author(s) -
Meier Eddi,
Frederiksen Kristen,
Nielsen Mogens,
Lembøl Hanne Løve,
Pedersen Henrik,
Hyttel John
Publication year - 1997
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199701)40:1<1::aid-ddr1>3.0.co;2-q
Subject(s) - muscarinic acetylcholine receptor , partial agonist , agonist , pharmacology , chemistry , nitrendipine , muscarinic acetylcholine receptor m1 , receptor , arecoline , muscarinic acetylcholine receptor m2 , endocrinology , muscarinic acetylcholine receptor m3 , bioisostere , medicine , muscarinic agonist , biology , in vitro , biochemistry , calcium , chemical synthesis
The arecoline bioisostere, Lu 25‐109‐T, displays a pharmacological profile of a partial muscarinic agonist with a several‐fold higher affinity for cortical M 1 receptors than for brain stem M 2 receptors and salivary glands M 3 receptors. The compound is selective for muscarinic receptors as it shows no or only low affinity for other receptor types. In functional assays Lu 25‐109‐T behaves as a partial agonist at the guinea pig ileum (M 1 /M 2 /M 3 ), at the rat superior cervical ganglion (M 1 and at cells transfected with cloned human ml muscarinic receptors and as an antagonist at guinea pig left atrium (M 2 ) and cultured cerebellar granule cells (M 3 ). Lu 25‐109‐T readily passes the blood‐brain barrier in mice and has a bioavailability of 42% at oral administration although with a short half‐life (t ½ =41 min). The results indicate that Lu 25‐109‐T is acting selectively on muscarinic receptors. In functional in vitro assays Lu 25‐109‐T acts as an M 1 (and m1) partial agonist and at the same time as an M 2 and M 3 antagonist. Drug Dev. Res. 40:1–16, 1997. © 1997 Wiley‐Liss, Inc.