Wolfgang Troger

PHASE I CLINICAL TRIALS WITH WAL 2014, A NEW MUSCARINIC AGONIST FOR THE TREATMENT OF ALZHEIMER'S DISEASE

The safety, tolerability and pharmacological activity of WAL 2014, a new centrally-acting M1 agonist were examined in two clinical studies (0.5-80 mg and 100-160 mg). Single increasing p.o. doses were administered to groups of 8 volunteers (6 verum, 2 placebo) each. Both studies were placebo controlled with single-blind observation within the respective dose groups. Vital functions (BP, HR, resp. rate) did not reveal any clinically significant substance-induced changes up to a dose level of 60 mg. A slight, but obvious increase in HR was measured with a dose of 80 mg and higher; a slight increase in systolic BP was registered at the dose levels of 120 and 160 mg. No substance-related alterations were observed in the laboratory tests (exception: a significant, reversible increase of the salivary fraction of alpha-amylase in 3 volunteers at the dose levels 100 mg-140 mg). The majority of volunteers reported an increased salivary secretion with doses of 40 mg and higher; this was confirmed by the greater volume of measured saliva. Furthermore, with doses of 100 mg upwards there were isolated reports of side effects such as a desire to urinate, a burning sensation on urination, increased lacrimation and nasal secretion, disturbances of accommodation, heartburn, rumbling of the stomach as well as cramps, nausea, diarrhoea, excessive sweating and palpitation. WAL 2014 did not cause any abnormal changes in the EEG. Dose dependent central effects were observed with 40, 60, 80, 100 and 140 mg treatments. Pharmacokinetic data indicate a rapid and good absorption and an absolute bioavailabitlity > or = 70%. The pharmacodynamic and side effects observed in both studies are regarded as being drug-dependent and might be due to the cholinergic activity of the compound and a weak sympathetic activation via M1 receptors. In summary, the substance did not produce any effects in the dose range tested to suggest further use in man might be inadvisable.

WAL 2014 FU (Talsaclidine) : A preferentially neuron activating muscarinic agonist for the treatment of Alzheimer's disease

The functional selectivity of WAL 2014 FU with regard to stimulation of the neuronal muscarinic M1 receptor subtype in vitro and in vivo is shown in different receptor preparations, isolated organ models, whole animal testing, and finally humans. From receptor binding experiments in membrane preparations from rat tissues and from Chinese hamster ovary cells expressing human muscarinic receptor subtypes, it can be delineated that the ratio between M1 and M2 (hm1 and hm2) is shifted in favour of the M1 receptor affinity, when compared to several classic muscarinic agonists such as carbachol, arecoline, and oxotremorine. The intermediate GTP‐shift of 7.5 for WAL 2014 FU in a M2 muscarinic receptor preparation (rat heart) indicates only partial agonistic activity at this subtype, carbachol (e.g., shows a shift of 51). Moreover, the ratio from agonist to antagonist receptor binding comparing the affinities using [3H]cis‐methyldioxolane and [3H]N‐methylscopolamine as radioligands, suggests only a partial agonist behaviour at M2 receptors, too.

In vivo consequences of M1-receptor activation by talsaclidine

The aim of this investigation in anaesthetized dogs was to provide direct evidence for an activation of the sympathetic nervous system by the muscarinic agonist talsaclidine (WAL 2014 FU). Intravenous infusion at a rate of 1 mg/kg/min increased plasma catecholamines and in particular epinephrine, thus indicating a predominant stimulation of the adrenals. Sympathetic activation was also indicated by increases in renal vascular resistance, an effect which was sensitive to alpha-adrenolysis. It is concluded that the sympathetic activation by talsaclidine is due to full agonism at the M1-receptor and the ability to cross the blood-brain barrier. As talsaclidine is less potent and only a partial agonist at M2- and M3-receptors many peripheral actions mediated by these receptor subtypes are functionally antagonized by the concomitant sympathetic activation.