Lone Jeppesen

Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice

Abstract Xanomeline is an M1/M4 preferring muscarinic receptor agonist which decreased psychotic behaviors in patients with Alzheimers disease, suggesting that xanomeline might be useful in the treatment of psychotic symptoms in patients with schizophrenia. The purpose of the present studies was, therefore, to compare the pharmacologic profile of xanomeline with that of known antipsychotic drugs. Electrophysiologically, xanomeline, after both acute and chronic administration in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced climbing in mice. However, unlike the dopamine antagonist antipsychotic haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline, like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance responding in rats, an effect which also was blocked by scopolamine. The present results thus demonstrate that xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomeline has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.

POTENTIAL ROLE OF MUSCARINIC RECEPTORS IN SCHIZOPHRENIA

The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M2/M4 receptors and an antagonist at M1, M3 and M5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice. d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.

Xanomeline compared to other muscarinic agents on stimulation of phosphoinositide hydrolysis in vivo and other cholinomimetic effects

Activation of muscarinic m1 receptors which are coupled to the phosphoinositide (PI) second messenger transduction system is the initial objective of cholinergic replacement therapy in Alzheimers disease. Thus, we evaluated the ability of the selective muscarinic receptor agonist (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydrolysis and compared it to a number of direct acting muscarinic agonists, two cholinesterase inhibitors and a putative m1 agonist/muscarinic m2 antagonist. Using a radiometric technique, it was determined that administration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating mediation by muscarinic receptors. The non-selective muscarinic agonists pilocarpine, oxotremorine, RS-86, S-aceclidine, but not the less active isomer R-aceclidine, also effectively stimulated PI hydrolysis in mice. Amongst the putative m1 agonists, thiopilocarpine, hexylthio-TZTP as well as xanomeline effectively stimulated PI hydrolysis, but milameline, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-induced PI stimulation, suggesting that they act as antagonists at PI-coupled receptors in vivo. The cholinesterase inhibitors, tacrine and physostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vivo PI hydrolysis. Xanomeline, hexylthio-TZTP and thiopilocarpine were relatively free of cholinergic side effects, whereas milameline, WAL 2014 and SKB 202026 produced non-selective effects. Therefore, these data demonstrate that xanomeline selectively activates in vivo PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomelines beneficial clinical effects on cognition in Alzheimers patients.

Muscarinic receptor agonists decrease cocaine self-administration rates in drug-naive mice.

(5R,6R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[ 3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M(2) and M(4) and antagonist mode of action at muscarinic M(1), M(3) and M(5) receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.

The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance

(5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane) (BuTAC) is a novel, selective muscarinic receptor ligand with partial agonist mode of action at muscarinic M2 and M4 and antagonist mode of action at M1, M3 and M5 receptor subtypes in cloned cell lines. BuTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for dopamine receptors, and parasympathomimetic effects in mice are produced only at doses well beyond the doses exhibiting the antipsychotic-like effects. In the present study we investigated the effects of BuTAC and the antipsychotic compounds clozapine, sertindole and olanzapine using one trial passive avoidance with mice as a model of learning and memory. Pharmacologically relevant doses of BuTAC and reference antipsychotics were identified, based on inhibition of apomorphine-induced climbing in mice as an assay measuring antidopaminergic potency. When ratios between the minimum effective dose (MED) for impairment of retention in passive avoidance and the MED for inhibition of apomorphine-induced climbing were calculated, BuTAC displayed a high ratio of >10, compared with clozapine (0.3), sertindole (3) and olanzapine (3). These data suggest that BuTAC is a potential novel antipsychotic which may have favourable effects on aspects of learning and memory.

Design and synthesis of novel PPARα/γ/δ triple activators using a known PPARα/γ dual activator as structural template

Abstract Using a known dual PPARα/γ activator (5) as a structural template, SAR evaluations led to the identification of triple PPARα/γ/δ activators (18–20) with equal potency and efficacy on all three receptors. These compounds could become useful tools for studying the combined biological effects of PPARα/γ/δ activation.

Muscarinic agonists exhibit functional dopamine antagonism in unilaterally 6-OHDA lesioned rats.

(5R,6R) 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]oc tane (PTAC) is a selective muscarinic ligand with high affinity for central muscarinic receptors, agonist mode of action at the muscarinic M2 and M4 receptor subtypes and substantially less or no affinity for central dopamine receptors. In the present study PTAC, as well as the muscarinic agonists oxotremorine, RS86 and pilocarpine, inhibited dopamine D1 and D2 receptor agonist induced contralateral rotation in unilaterally 6-OHDA lesioned rats. The dose of SKF 38393 used to induce contralateral rotation also caused an intense Fos protein immunoreactivity in the rat dorsolateral striatum on the lesioned site which was inhibited by PTAC indicating that the inhibition of rotation by PTAC was not due to non-specific peripheral side effects.

Selective PPAR agonists for the treatment of type 2 diabetes

Abstract:  Type 2 diabetes is a metabolic disease characterized by increased plasma glucose and insulin as well as dyslipidemia. If left untreated, chronic diseases will develop that are associated with neuropathic damage and higher mortality risk. Using a rational drug design, novel compounds have been developed that selectively activate the human PPAR receptors, leading to lessening of hyperglycemia and hyperinsulinemia as well as reduction of lipid levels in conjunction with an increase of the beneficial HDL‐cholesterol. These PPAR agonists showed increased potency and efficacy compared to previously marketed insulin sensitizers. Lead compounds with desirable pharmacokinetic properties were chosen for further testing in several animal models. The in vivo activity of some synthetic ligands, capable of activating two or all three members of peroxisome proliferator‐activated receptors (PPAR) family of receptors, suggested that they may have improved efficacy in type 2 diabetes therapy. Here, we briefly summarize the development of some novel PPAR agonists identified by our group in recent years.

Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic M1 receptor activation

Series of analogs to the functional m1 selective agonist, xanomeline (hexyloxy-TZTP), were evaluated for their in vitro m1 efficacy in cell lines transfected with the human m1 receptor. Systematic variation of the side chain and the azacyclic ring led to the discovery of potent muscarinic agonists with robust m1 efficacy, all having the phenylpropargyloxy/thio as the side chain. The most selective compound was the phenylpropargylthio-[3.2.1] endo analog 28, which is a potent and efficacious m1 agonist with no m2 activity.

Mesolimbic selective antipsychotic arylcarbamates

Abstract 4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidine has been linked to various arylcarbamates to obtain compounds having affinity for dopamine-D 1 and -D 2 , serotonin 5HT 2A and α 1 -adrenoceptors. When linkers with restricted flexibility are used, the biological activity is reduced indicating that a bended conformation is needed in this series of bioactive molecules. Compounds with a relatively low D 2 /5HT 2A affinity ratio in receptor binding experiments and high affinity for the α 1 -adrenoceptors exhibit a pharmacological profile which suggests a preferential effect on the mesocorticolimbic dopaminergic system and an ‘atypical’ antipsychotic activity.