Pharmacological in vitro characterization of the arecoline bioisostere, Lu 25-109-T, a muscarinic compound with M1-agonistic and M2/M3-antagonistic properties
✍ Scribed by Eddi Meier; Kristen Frederiksen; Mogens Nielsen; Hanne Løve Lembøl; Henrik Pedersen; John Hyttel
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 210 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0272-4391
No coin nor oath required. For personal study only.
✦ Synopsis
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 m1 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.