A Multitransmitter Approach to Dementia Treatment
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CNS Drug Reviews Vol. 8, No.2, pp. 143–158 © 2002 Neva Press, Branford, Connecticut Ensaculin (KA-672 × HCl): A Multitransmitter Approach to Dementia Treatment Robert Hoerr1 and Michael Noeldner2 1Clinical Research Department and 2Department of Pharmacology, Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany Key Words: Ensaculin—Benzopyranone—Dementia—Neurotransmitters—Me- mory—Neuroprotection—5-HT1A—5HT7 —NMDA antagonists. ABSTRACT Ensaculin, a novel benzopyranone substituted with a piperazine moiety, showed memory-enhancing effects in paradigms of passive and conditioned avoidance in both normal and artificially amnesic rodents. It exhibited neuroprotective activities in an NMDA toxicity model and neurotrophic effects in primary cultured rat brain cells. The compound could be characterized as a weak NMDA receptor–operated channel blocker. In receptor-binding studies, ensaculin was found to have high affinities to serotonergic 5-HT1A and 5-HT7 receptors, adrenergic á1, and dopaminergic D2 and D3 receptors. Due to its unique pharmacodynamic profile, ensaculin may have potential as an antidementia agent acting on various transmitter systems. INTRODUCTION Alzheimer’s disease (AD) is a neurodegenerative disorder that predominantly affects aged people. It is the most frequent cause of dementia, thus gaining increasing importance as the population continues to age. Even though extensive research has been directed to- wards the understanding of this devastating illness, the formal and causal interrelation- ships of its pathogenetic determinants are still an enigma. The most distinctive morphological features of AD are amyloid deposition resulting in neuritic plaques, the formation of neurofibrillary tangles consisting of hyperphosphory- Address correspondence and reprint requests to: Dr. Robert Hoerr, Clinical Research Department, Dr. Willmar Schwabe GmbH & Co., Willmar-Schwabe-Strasse 4, 76227 Karlsruhe, Germany. Tel: +49 (721) 4005-492; E-mail: [email protected] 143 144 R. HOERR AND M. NOELDNER lated tau protein, neuronal degeneration with a subsequent loss of synapses, and general cortical atrophy. At a biochemical level, AD is characterized by impairments in neurotransmitter systems. The cholinergic system is probably the neurotransmitter system most affected. The activity of choline acetyltransferase (ChAT), the key enzyme in acetylcholine syn- thesis, is reduced by 50–85% in various cortical regions and the hippocampus of AD pa- tients. Moreover, muscarinic receptor binding is decreased in the frontal cortex. The bio- chemical changes in this transmitter system, such as reductions in cortical ChAT activity and cerebrospinal fluid (CSF) cholinesterase activity, correlate with both the tangle load in the frontal cortex and the severity of dementia symptoms prior to death (8,26). The concentration of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) has been shown to be lowered in cortical areas and the basal ganglia by up to 37 and 54%, respectively (26,8). Norepinephrine and dopamine concentrations are reduced in cortical areas of AD brains (26,8), and the density of striatal D2 dopaminergic receptors is decreased (25). The quantitatively most important neurotransmitter system in the cerebral cortex, the glutamatergic system, is also affected by AD, with a decrease in glutamatergic N-methyl- D-aspartate (NMDA) receptors, predominantly in the frontal cortex (4,26,28). On the one hand, the physiological stimulation of the NMDA receptors has a major role in memory formation. On the other hand, over-stimulation may cause serious damage to neurons by increasing the influx of calcium ions (16). Cellular energy deficiency, which is likely to prevail in AD due to a disruption of the oxidative glucose metabolism, may render neurons particularly vulnerable to (relative) glutamatergic over-stimulation by compro- mising the channel-blocking action of magnesium ions. In regard to neuropeptides, somatostatin levels have been found to be decreased (1,26) in the cortex of AD patients. While nerve growth factor (NGF) concentrations appear to remain unchanged, NGF receptor defects probably arise (9). Possible treatment strategies for AD include inhibition of ß-amyloid peptide secretion and/or plaque formation, pre- vention of tau hyperphosphorylation and fibrillary tangling, activation of neurotransmitter systems, inhibition of NMDA-mediated neurotoxicity, oxygen free radical scavenging, and restoration of the oxidative glucose metabolism. The most advanced treatment options are based on cholinergic stimulation and are justified by the marked deficits in this neuro- transmitter system and its close link to cognitive functioning. While cholinesterase inhi- bitors have proven to be modestly effective (2), attempts on direct muscarinic M1 receptor stimulations by agonists have been disappointing. Low-affinity blockers of the NMDA receptor-mediated ion channel and substances with antioxidant properties have yielded promising results in clinical trials. Given the limited treatment success achieved with drugs selectively directed towards one neurotransmitter system, the idea of concurrently addressing a range of the neuro- transmitter systems affected by AD is intriguing. Ensaculin (KA-672 × HCl) was identified as a compound with a unique profile of pharmacodynamic effects on the central nervous system (CNS) when a series of syntheti- cally modified compounds derived from the central structure of natural coumarins were screened for their potential therapeutic value. CNS Drug Reviews, Vol. 8, No. 2, 2002 ENSACULIN 145 Fig. 1. Chemical structure of ensaculin (KA-672.HCl). CHEMISTRY The chemical structure of ensaculin (KA-672, 7-methoxy-6-{3-[4-(2-methoxyphenyl)- 1-piperazinyl]propoxy}-3,4-dimethyl-2H-1-benzopyran-2-one) corresponds to a benzopy- ranone with a piperazine moiety (Fig. 1). It is crystallized as hydrochloride salt, which has the most favorable physicochemical properties. Ensaculin hydrochloride is a white, crystalline powder with a molecular weight of 489.02 and a melting point of about 240°C (decomposition). It usually contains 3–4% water. Its solubility in water is 3,000 ppm at room temparature. The structure of ensaculin is evident from the starting materials entering the synthetic pathway, and it has been verified by elemental analysis, infrared and mass spectrometry, 1H and 13C NMR spectroscopy, and x-ray structure analysis. PHARMACOLOGY Modulation of Memory Functions The antidementia activity of ensaculin was initially detected in a rat conditioned avoidance (CAR) and a mouse passive avoidance (PAR) model (15) and later confirmed in different variations of these animal models. 1. Reversal of scopolamine-induced amnesia in a passive avoidance paradigm Reversal of scopolamine-induced amnesia for passive avoidance task is widely used to screen putative cognition enhancers. The method described by De Wied (7) was used with minor modifications. In short, mice were placed in a light compartment connected by a hole to a large dark compartment. After the mice enter the dark compartment they get a foot shock through the steel grid floor. Immediately after termination of the foot shock the animals were removed from the dark compartment. The same manipulation was repeated after 24 h, 7 days, and 14 days without foot shock (retention test). The latency time CNS Drug Reviews, Vol. 8, No. 2, 2002 146 R. HOERR AND M. NOELDNER 150 *P < 0.05 125 Student'st -test 100 (sec) 75 Iatency 50 25 0 0.0 0.1 0.3 1.0 mg/kg ensaculin Fig. 2. Effects of ensaculin on passive avoidance 24 h latency in scopolamine-induced amnesia (acquisition). Values are means ± S.E.M. of at least eight animals per group. (before entry in the dark compartment) was registered. Intact animals remember the foot shock and do not change compartments during the retention tests. After induction of am- nesia (scopolamine or electroshock) animals do not remember the foot shock and enter the dark compartment within a few seconds. The tests were performed in three modifications: (1) acquisition, ensaculin was administered 1 h before the first learning session; (2) memory consolidation, ensaculin was administered immediately after the first session; (3) memory retrieval, ensaculin was administered on day 2, 1 h before the retention test. In the case of scopolamine amnesia, scopolamine hydrochloride, 1 mg/kg, was applied subcutaneously (s.c.) 30 min before the training session. In the case of electroshock amnesia, a shock was applied by cornea electrodes (50 mA, 0.2 sec) immediately after the training session. The activity profile of ensaculin in these models is summarized in Figs. 2 and 3. It an- tagonized scopolamine- and electroshock-induced amnesia in mice after oral adminis- tration in a dose range between 0.1 and 1 mg/kg. A U-shaped dose-response relationship was found with significantly (P < 0.05) longer latencies for the 0.3 mg/kg dose compared with drug-free controls. In summary, ensaculin caused antiamnesic effects by increasing the latency on passive avoidance response in scopolamine-induced and to a lesser degree in electroshock-induced amnesia. Some of these effects were maintained for 14 days after single administration of the drug (15). 2. Effects of ensaculin on learning ability in intact animals In a second set of experiments, the effects of ensaculin on learning ability in non- amnesic animals were investigated. Mice were tested in the PAR test described above (without amnesia) and rats were tested in a CAR paradigm described by De Wied (6)