Microsoft word - upd47.doc

homology between these subtypes and their co- currently in clinical development for the treatment of cognitive disorders and schizophrenia. A Arai et al heterodimerization physiologically important. She alsodemonstrated that disparate Bmax values obtained withdifferent D2 receptor ligands could be explained byselective binding of a particular compound to themonomer, dimer or both D2 species. Dimerization ofthe D2 was narrowed down to occur in thetransmembrane domain 1 to 5, not 6 to 7 and involve adisulfide bond between monomers.
Signaling by the heterodimeric GABAB
receptor
Ken Jones (Synaptic Pharmaceutical Corp, Paramus,NJ, USA) highlighted the role of the GABAB receptorassembly as a regulator of transmitter release in theCNS. It provides an attractive target for the treatmentof epilepsy, anxiety, depression, cognitive defects, andnociceptive disorders. Heteromerization of GABAB-R1and GABAB-R2 subunits is needed for the formation ofa functional GABAB receptor. Each subunit has a 30amino acid domain of its intracellular C-terminaldomain that regulates heterodimer formation. GABAB-R1 peptides alone form unstable homodimers, whereasGABAB-R2 peptides were largely unstructured.
Functionally, the heterodimerization of GABABsubunits produced effective Na+/H+ exchange intransfected cells.
Dimerization, and perhaps even more complexassociations between similar and different receptors,can provide an additional way to regulate of G protein-coupled receptors. This formation of homo- andheterodimerization can occur between differentdomains of the 7TM receptors and can involvedisulfide or other robust molecular interactions. Thebelief is that these dimerizations can occur in cellswhere various types of G protein-coupled receptors arenaturally co-localized in the membrane. It can beexpected that receptors that form dimers will expressdifferent sensitivity and selectivity to both agonists andantagonists at one or both units of the dimer. Finally,these associations will have important effects on thefunctional outcome of receptor-ligand interactions [RefIDdb].
Society for Neuroscience 29th Annual
Meeting (Part XI)
23-28 October 1999, Miami Beach, FL, USA
Reported by Dr Chris G Parsons, Merz & Co GmbH,
Frankfurt, Germany
Excitatory amino acids
AMPA receptor positive modulators
AMPAkines (Cortex Pharmaceuticals Inc) are
positive modulators of AMPA receptors which are
ID weekly highlights Copyright Current Drugs Ltd, November 1999. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK• http://www.current-drugs.com (University of California, Irvine, CA, USA) M Brenner et al, M Wienrich et al, R Palluk et al and T presented in vitro data with novel alkylated Christensen et al (all Boehringer Ingleheim Corp, benzothiadiazides as positive AMPA receptor Ingelheim am Rhein, Germany) presented posters on modulators. One such compound, D1, completely Boehringer Ingelheim Corp's novel, combined, non- blocked neuronal desensitization with an EC competitive AMPA receptor antagonist/voltage-gated of 3.6 µM, and prolonged deactivation kinetics 10- sodium channel blocker, BIIR-561-CL. Cortical neuronal fold in response to a 1 ms application of 1 mM responses to kainate were antagonized by BIIR-561-CL 50 = 8.5 µM) in a non-competitive, non-use- and non- This compound also enhanced [³H]fluorowillardine voltage-dependent manner, similar to the 2,3- benzodizepines. Human GluR1/2 receptor responses to 1 effect appeared to be competitive with the 2,3- mM glutamate were also antagonized with an IC50 value benzodiazepine GYKI-52466 (Egis Gyogyszergyar of 16.8 µM and no effect on response kinetics. The RT). In contrast to cyclothiazide, D1 showed no potency of BIIR-561-CL was increased at acidic pH preference for flip/flop isoforms of AMPA receptors.
indicating greater effectiveness under ischemic D1 slowed the decay of AMPA receptor-mediated conditions. BIIR-561-CL had a good therapeutic index of fEPSPs whereas another compound, 16h, increased around 10 against MES-induced tonic convulsions their amplitude. The development of 16h has been compared to motor impairment in the rotarod. AMPA- stopped as it induced convulsions in vivo.
induced lethality was blocked with an ID50 value of 4.6mg/kg. Four doses of 30 mg/kg sc decreased mortality,from 33.6% to 14%, following 10 min of global ischemia AMPA receptor antagonists
in rats, and provided around 50% cortical protection in a M Takahashi et al (Yamanouchi Pharmaceutical Co permanent rat MCA occlusion model (48 hour survival); Ltd, Tsukuba, Japan) showed how the competitive two doses of 60 mg/kg provided 30% protection in a AMPA receptor antagonist YM-872 (Yamanouchi permanent murine MCA occlusion model. BIIR-561-CL Pharmaceutical Co Ltd) was only moderately effective, 7.2 mg/kg/h iv for 24 h provided good protection in a offering just 28% protection in a permanent model of transient MCA occlusion model in the rat (1 hour middle cerebral artery (MCA) occlusion in rats when occlusion) when damage was assessed after 7 days administered for 24 h at 20 mg/kg/h, starting 10 min survival. Lower doses of 2 and 4 mg/kg/h were also after surgery. When administered for 4 h, the drug was effective in a similar paradigm in permanent MCA ineffective when assessed 24 h later.
occlusion. However, it should be noted that BIIR-561-CL10 mg/kg sc only had a therapeutic time window of 1 SYM-2189 (Annovis Inc) was shown, by SN Irizarry hour following the onset of permanent MCA occlusion.
et al (Yale University School of Medicine, NewHaven, CT, USA) to be a non-competitive and NR2B selective antagonists
selective AMPA receptor antagonist with an IC50 value ML Weber et al (Parke-Davis Pharmaceutical Research, of 4.5 µM against kainate-induced currents in cultured Ann Arbor, MI, USA) produced data showing that the spinal neurones. This block was not effected by the NR2B selective NMDA receptor antagonist CP-101606 presence of the positive modulator cyclothiazide and (Pfizer Inc) had no effect on hippocampal LTP at 10 µM, seemed to be specific for AMPA receptors, ie, it had whereas the same concentration reduced zero Mg2+- no effect on GluR6/KA2 or NMDA receptors.
induced epileptic activity by 50%, indicating that thiscompound could show a somewhat better separation Ca2+ permeable AMPA receptors (lacking edited between physiological and pathological activation of GluR2) have been implicated to play a role in various NMDA receptors than competitive antagonists such as glutamate pathologies, although it should be stressed CPP and APV. However, further concentrations must be that these receptors are also crucial for physiological tested to assess whether this is a quantitative or qualitative events in inhibitory interneurones in, eg, the hippocampus. EW Harris et al (AstraZeneca plc,Rochester, NY, USA) presented data which showed Co-101244 (CoCensys Inc) is also a selective NR2B that MLV-5860 (Tokyo Metropolitan Institute of antagonist (IC50 = 24 nM in Xenopus oocytes). It was Medical Science) non-competitively blocked Ca2+ shown that this compound had no effect in the acetic acid writhing model but decreased both the early (3 µM. This effect was use-dependent and occluded by mg/kg) and late (10 mg/kg) phases of the formalin the channel blocker Jorospider toxin. MLV-5860 had response; the same doses had no ataxic effects but little effect on NMDA receptor subtypes expressed in produced a moderate increase in locomotor activity. On Xenopus oocytes at 10 µM. However, previous data the basis of these data, it was proposed that Co-101244 shown that low nM concentrations of MLV-5860 has an improved analgesic/side-effect profile.
analogs inhibit the binding of [³H]MK-801 Parke-Davis & Co is trying to improve the profile of its NR2B selective antagonists, for use in treating ID weekly highlights Copyright Current Drugs Ltd, November 1999. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK • http://www.current-drugs.com Parkinson's disease, by increasing potency and oral Institut Henri Beaufour, Les Ulis, France), showed a activity and reducing first past metabolism. JL Wright non-significant, moderate trend for improvement at the et al (Parke-Davi Pharmaceutical Research, Ann highest dose tested of 0.02 mg/kg iv. In another study Arbor, MI, USA) presented data on 20 novel by M Muzet (Forenap-Pharma, Rouffach, France) and compounds. One compound had an IC50 value of 5 nM colleagues from Beaufour-Ipsen, the maximum at NR2B receptors, whilst having far less effect at tolerated dose in healthy volunteers was 0.04 mg/kg iv, NR2A (IC50 = 35 µM) and NR2C receptors (IC50 > 100 and 'classical' CNS side effects, such as euphoria, µM) but still retained some activity at α1 receptors dysphoria and psychotomimetic effects, were seen at intermediate doses (0.01 to 0.02 mg/kg iv) with 50 value, assessed with [³H]prazosin binding, was 0.5 µM). This compound potentiated the effects of L- sedation noted at higher doses (0.05 mg/kg iv).
DOPA in a rat model of Parkinson's disease after oraldosing at 10 and 30 mg/kg.
Partial trapping is a property of moderate to low affinityuncompetitive NMDA receptor antagonists and has been BA Chizh et al (Grünenthal GmbH R&D, Aachen, proposed to account for their better therapeutic profile, as Germany) provided evidence that the antinociceptive a proportion of channels would release blocker in the effects of the NR2B selective antagonist ifenprodil absence of agonist and thus be available for subsequent (Synthelabo) are mediated at a supraspinal site whereas transient synaptic activation by glutamate. Astra Arcus those of the uncompetitive antagonists (+)MK-801 and AB seems to be following this strategy to develop better memantine are mediated at the spinal level. Thus, in NMDA receptor antagonists. G Mealing (Institute for contrast to the latter two compounds, iv ifenprodil had Biological Sciences, National Research Council of no effect on wind-up or microelectrophoretic responses Canada, Ottawa, Canada) and colleagues from Astra of single spinal neurones to NMDA in spinalized Arcus USA, presented data from a wide range of animals. However, the drug was effective against compounds and showed various levels of partial trapping wind-up and in reducing baseline responses in spinally that were not related to logP values, indicating that a intact animals at similar doses to those producing lipophyllic pathway can not account for this effect.
effects in the Freund's complete adjuvant model ofunilateral hind paw hyperalgesia.
Ischemic tolerance may be an endogenous mechanismthat develops after mild insults to protect the CNS against Conantokin-G (Annovis Inc) was stated by L Chicoine subsequent larger ischemic episodes. This process is (Cognetix Inc, Salt Lake City, UT, USA) to be in thought to be NMDA receptor-mediated, which might be development to treat severe epilepsy. This conopeptide counter indicative for the use of NMDA receptor was reported to be a selective antagonist of NR2B antagonists in, eg, vascular dementia. Systemic administration of the mitochondrial toxin 3-NP (20 mg/kg receptors (30 µM had almost no effect) using a ip) was also able to induce ischemic tolerance, assessed flourometric assay. It also showed colocalisation to ex vivo 24 h later in hippocampal slices exposed to 7 mins NR2B-containing neurones in cortical cultures using of complete hypoxia/hypoglycemia. However, the moderate-affinity uncompetitive NMDA receptorantagonist memantine (20 mg/kg/day sc via osmotic Merck KGaA is also developing NR2B selective minipumps, starting 48 h prior to 3-NP) actually antagonists based around the structure of its eliprodil enhanced ischemic tolerance in this ex vivo model, as (Synthelabo) analog, EMD-95885, as was disclosed by presented by T Frankiewicz and CG Parsons (Merz & Co R Gottschlich et al (Merck KGaA, Darmstadt, Morphine tolerance
Uncompetitive NMDA receptor antagonists
The glycineB antagonist MRZ-2/576 (Merz & Co Gacyclidine (Protec; Beaufour-Ipsen) is a PCP analog GmbH) and, to a lesser degree, the moderate-affinity with low nM affinity at the MK-801 site, previously channel blocker MRZ-2/579 (Merz & Co GmbH), both claimed to be a potent neuroprotective agent in animal at 1 to 10 mg/kg ip, significantly increased morphine models of spinal cord trauma, which is devoid of side (1 to 20 mg/kg sc) peak analgesia and duration in the effects. It was effective as a 1 mg/kg iv bolus when tail-flick test. The development of morphine tolerance given 10 mins post trauma and was as effective as (20 mg/kg, 8 days, once a day) was also attenuated by CNS-1102 (aptiganel; Oregan Health Sciences both MRZ-2/579 (1 to 30 mg/kg) and MRZ-2/576 (10 University) and (+)MK-801. Bolus plus infusion did mg/kg). Moreover, acquisition of iv morphine self- not increase protection. Moreover, lower (0.3 mg/kg) administration in drug- and experimentally-naive mice and higher doses (3 mg/kg) had absolutely no effect in was inhibited by pretreatment with MRZ-2/579. These the same model. Initial data from phase II trials in results, presented by M Sopala (Merz & Co GmbH) et spinal cord injury, presented by M Tadié et al, and al further suggest that NMDA receptor antagonists severe traumatic brain injury, presented by P may have the capacity to increase the therapeutic safety D'Árbigny et al (both teams from Beaufour-Ipsen, and effectiveness of opioid analgesics.
ID weekly highlights Copyright Current Drugs Ltd, November 1999. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK• http://www.current-drugs.com Dextromethorphan, memantine and MRZ-2/579 dose- membrane bound metallopeptidase NAALADase is co- dependently (5 to 10 mg/kg) inhibited the development of localized with NAAG in the CNS and converts NAAG morphine tolerance following 6 days bid of 10 mg/kg to NAA and glutamate. It seems likely that NAAG is morphine injections, as shown by P Popik (Institute of also a weak partial agonist at NMDA receptors with Pharmacology, Polish Academy of Sciences, low intrinsic activity, and an agonist at mGluR3 Sienkiewicza, Poland) et al. All three antagonists receptors. As such, inhibition of NAALADase could enhanced the extinction of morphine tolerance once be useful in numerous CNS disorders associated with established. Furthermore, memantine and MRZ-2/579 disturbances in glutamatergic transmission by were also able to reverse morphine tolerance in the decreasing the concentration of glutamate and continuing presence of morphine even when treatment increasing the concentration of NAAG. Guilford began after tolerance had already been established. These Pharmaceuticals Inc has followed this approach, as data indicate that low affinity, clinically available and/or described in a poster by B Brown (Guilford therapeutically promising NMDA receptor antagonists, Pharmaceuticals Inc, Baltimore, MD, USA) et al. The may be used to inhibit ongoing morphine tolerance.
NAALADase inhibitor 2-PMPA (GuilfordPharmaceuticals Inc), at 50 mg/kg ip daily for 2 weeks, MRZ-2/579, administered via osmotic minipumps at reduced both phases of formalin-induced flinching 40 mg/kg/day sc preventing the development of behaviour in rats, and was more effective on the late tolerance to the analgesic effects of morphine (28.8 phase as expected for agents selectively interfering mg/kg/day via osmotic minipumps), was assessed over with the induction of chronic pain states. Similarly, three days via repetitive testing of mechanical paw acute dosing with 2-PMPA 30 or 100 mg/kg was withdrawal thresholds. AK Houghton (University of effective in the acetic acid writhing model in mice.
Bristol, UK) et al concluded that moderate affinity Similarly, BS Slusher (Guilford Pharmaceuticals Inc) NMDA channel blockers such as MRZ-2/579 may et al showed that two NAALADase inhibitors, prove useful in attenuating the development of administered daily over 12 weeks, attenuated tolerance to morphine and so reducing morphine hyperalgesia observed in streptozotocin treated rats, a requirement in clinical pain conditions.
model of diabetic neuropathy. They also improvedmotor and sensory nerve conduction velocities for the Glycine site antagonists
whole period studied. According to TP Hicks (Guilford Glycine is a co-agonist for NMDA receptors and there is Pharmaceuticals Inc) et al, neuroprotective still considerable hope that specific antagonists at the concentrations do not seem to affect normal physiological transmission in in vitro models.
B site might block the pathological activation of NMDA receptors whilst leaving their physiologicalactivation intact. RL Balster et al (Medical College of Neuronal nicotinic antagonists
Virginia, Viginia Commonwealth University, Richmond, It is now clear that methadone is not only a µ opioid VA, USA) tested several glycineB antagonists in rats receptor agonist but also blocks NMDA receptors in an trained to discriminate 2 mg/kg PCP or NPC-17742 uncompetitive, non-stereoselective manner. Y Xiao (Scios Inc) 4 mg/kg from saline. (+R)HA-966 and L- (Georgetown University School of Medicine, 701324 (both Merck & Co Inc), MDL-103371 and MDL- Washington DC, USA) et al showed that both 105519 (both Hoechst Marion Roussel Inc), MRZ-2/571 enantiomers of methadone also act as antagonists of and MRZ 2/576 (both Merz & Co GmbH), MDL-104472 α3β4 neuronal nicotinic receptors, with an IC50 value and ACEA-0762 all failed to fully substitute for PCP or of 1.8 to 2.5 µM assessed with nicotine-evoked 86Rb+ NPC-17742 at behaviorally-active doses. The researchers efflux. This effect is probably non-competitive as the conclude that these glycineB antagonists are less likely to produce the adverse behavioral toxicity seen with high [³H]epibatidine binding was only effected at much affinity channel blockers and competitive NMDA higher concentrations (> 500 µM). Similarly, T Gupta (Georgetown University School of Medicine) et alshowed that the diuretic amiloride, an epithelial Na+ In addition, T Kivastik and S Liljequist (Karolinska channel blocker, could block neuronal nicotinic α3β4 Institute, Stockholm, Sweden) showed that the Merck receptors in a rapid, strongly voltage-dependent (IC50 compound L-701324 (2, 4 or 8 mg/kg ip) did not affect at 120 mV = 68 µM, IC50 at -40mV = 215 µM) and microdialysate levels of dopamine in the nucleus use-dependent (tail currents) manner.
accumbens and was also without effect on dopamineelevation caused by cocaine (30 mg/kg ip).
Zyban (bupropion; Glaxo Wellcome plc) is an atypicalantidepressant with an unknown mechanism of action, NAALADase inhibitors
which is currently being used in smoking cessation N-Acetyl-aspartyl-glutamate (NAAG) is abundant in therapy. JE Slemmer et al (Medical College of the mammalian CNS which has led to the hypothesis Virginia) showed that buproprion blocks α4β2, α3β2 that this dipeptide is the storage form of glutamate; the and α7 receptors expressed in Xenopus oocytes with ID weekly highlights Copyright Current Drugs Ltd, November 1999. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK • http://www.current-drugs.com IC50 values of 8, 1.3 and 60 µM, respectively. These illness, especially in the young, and is an important effects were non-competitive but voltage-independent, public health problem. An overview of mood disorders and were much more potent following preincubation, and suicide was delivered which included scientific, indicating that the drug may interact with the closed literary, clinical and personal perspectives and was not too optimistic with the currently available drugs.
Cocaine was also shown by MM Francis (Cornell The special lecture on 'Long-term potentiation and University Veterans Medical Center, Ithaca, NY, USA) long-term depression', delivered by RC Malenka et al to block neuronal nicotinic receptors with the (Stanford University School of Medicine, CA, USA) focused on the continuation of considerable interest 50 values: α3β2 = 50 µM; α3β4 = 8 µM; α2β2 = 30 µM; and, α4β2 = 10 µM. The effects at because of the putative roles of these processes in the α3β4 receptors were strongly voltage-dependent, modification of neural circuits during learning whereas those at α4β2 receptors were weakly voltage- development. The cellular and molecular mechanisms dependent. Ketamine also blocked currents mediated underlying these phenomena have been reviewed, and via α4β4 receptors expressed in Xenopus oocytes with apparently conflicting results within the field were covered. Altogether this subject reflects the accepted 50 value of 0.24 µM in a use-dependent manner.
view on the electrophysiological approach to learning.
The non-selective neuronal nicotinic receptorantagonist mecamylamine (0.1 or 0.3 mg/kg po) had Ophthalmology
anxiolytic- and antidepressant-like activity in the The Warner-Lambert Lecture, 'A deep look into eye elevated plus maze and Porsolt test, respectively, morphogenesis and evolution', was delivered by W whereas higher doses (1 to 3 mg/kg) were without Gehring (Biozentrun, University of Basel, Switzerland) effect. Similarly, 0.1 mg/kg was able to blunt and focused on the Pax-6 gene. This gene has been elevations in plasma corticosteriods. It was proposed, identified as a master control gene for eye by Shytle et al (University of South Florida College of morphogenesis. By switching on this single gene Medicine, Tampa, FL, USA), that these effects may ectopically, a cascade of some 2500 genes is initiated underlie the usefulness of mecamylamine in treating that leads to the functional ectopic eyes. Several emotional and behavioral syndromes, such as subordinate target genes have been identified. Since Pax-6 genes have been found from flat worms to man,the lecture proposed a monophylectic origin in the eye;while clearly basic in its concept, this lecture opens up Society for Neuroscience 29th Annual
a vast number of options for animal studies aimed at Meeting (Part XII)
developing therapeutic protocols in ophthalmology.
23-28 October 1999, Miami Beach, FL, USA
Alzheimer's disease
In the symposium on 'Developmental mechanisms in Introduction
the pathogenesis of neurodegenerative diseases', MF The Annual meeting of the Society of Neuroscience is Mehler (Albert Einstein College of Medicine, Bronx, the most important meeting worldwide in the field of NY, USA) focused on cellular genes that are mutated neuroscience and neurochemistry. This year it attracted in several key neurodegenerative diseases and that approximately 25,000 US and International attendees, code for proteins with complex neurodevelopmental and a very impressive exhibition of state-of-the-art expression patterns. These and other experimental equipment, books and custom-design offers for findings suggest that disease pathogenesis may involve shortcuts in the long pathway that involves alterations in fundamental developmental mechanisms.
neuroscience research. The meeting is far to large to be This symposium explored how specific disease covered by one person; however, several highlights mutations in progenitor cell subtypes during critical emerged, part of which are tightly linked with new stages of neural induction, regional patterning and drug development or with basic research aimed to lineage maturation could alter cellular signaling, fate achieve such goals. In the following report some of decisions and bioenergetics in ways that predispose to these highlights are briefly summarized.
late-onset regional neuronal degeneration, a hallmarkof these pervasive disorders. The linkage between Mood modulators
development and deteriorative processes in the nervoussystem becomes gradually tighter, which promises new The 'Presidential Special Lecture' was delivered by K and interesting findings in this newly developing Redfield Jamison (Johns Hopkins University, subject. The special lecture on 'The neural basis of Baltimore, MD, USA) and focused on mood disorders.
vocal learning in songbirds' was delivered by AJ Both depression and manic-depressive illness are Doupe (University of California San Francisco, CA, common, treatable, and potentially lethal; suicide is the USA) and focused on songbirds providing a useful not uncommon outcome of severe untreated psychiatric system for investigating neural substrates sensory and ID weekly highlights Copyright Current Drugs Ltd, November 1999. ISSN 1365-5884 Middlesex House, 34-42 Cleveland Street, London W1P 6LB, UK• http://www.current-drugs.com

Source: http://www.chrisparsons.de/Chris/Acrobat/Parsons_1999d.pdf