WAL 2014--a muscarinic agonist with preferential neuron-stimulating properties.
The ability of WAL 2014 to elicit muscarinic responses was investigated in various in vitro and in vivo models. In CHO cells transfected with human m1- or m3- receptor genes, WAL 2014 was clearly more effective in stimulating the M1-mediated PI response. In isolated tissue preparations, WAL 2014 exhibited full agonist properties in the rabbit vas deferens (putative M1 receptor) and behaved like a partial agonist at M2 receptors in the atrium and M3 receptors in the ileum of guinea-pigs. In the pithed rat, in which the increase in blood pressure is mediated through a stimulation of M1 receptors in sympathetic ganglia, WAL 2014 produced a full dose response curve, whereas the reference compounds RS 86 and arecoline exhibited a bell-shaped behaviour. This is in accord with the view that WAL 2014 selectively activates M1 receptors in sympathetic ganglia, whereas conventional agonists in the same dose range stimulate both ganglionic M1 and vascular M3 receptors. The preferential neuron-stimulating properties were confirmed by EEG recording in the rabbit, in which muscarinic activation occurred at doses similar to those for ganglionic stimulation in the pithed rat. On the other hand, higher doses of WAL 2014 were needed to elicit muscarinic effects in peripheral effector organs, i.e. bradycardia, urinary bladder contraction and increase in airway resistance. It is concluded that WAL 2014 due to its preferential neuronal activity is a promising candidate for a cholinergic substitution therapy in Alzheimer's disease.
Ensinger
H A
HA
Boehringer Ingelheim KG.
Doods
H N
HN
Immel-Sehr
A R
AR
Kuhn
F J
FJ
Lambrecht
G
G
Mendla
K D
KD
Müller
R E
RE
Mutschler
E
E
Sagrada
A
A
Walther
G
G
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003655:Decerebrate State; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010277:Parasympathomimetics / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects; D014162:Transfection
D010277:Parasympathomimetics; D011812:Quinuclidines; D011976:Receptors, Muscarinic; C079885:talsaclidine fumarate