ABSTRACT
We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N-(6-methyl-1,3-benzoxazol-2-yl)-3',5'-dihydro-4-azaspiro[bicyclo[2.2.2]octane-2,4'-imidazole]-2'-amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors.
Subject(s)
Guanidine/pharmacology , Quinuclidines/pharmacology , Spiro Compounds/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/agonists , Dose-Response Relationship, Drug , Guanidine/analogs & derivatives , Guanidine/chemistry , Humans , Molecular Structure , Quinuclidines/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
Patients with schizophrenia show marked deficits in processing sensory inputs including a reduction in the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation. Such deficits are not readily demonstrable at other input frequencies. Acute administration of NMDA antagonists to healthy human subjects or laboratory animals is known to reproduce many sensory and cognitive deficits seen in schizophrenia patients. In the following study, we tested the hypothesis that the NMDA antagonist MK-801 would selectively disrupt steady-state gamma entrainment in the auditory cortex of urethane-anesthetized rat. Moreover, we further hypothesized that nicotinic receptor activation would alleviate this disruption. Auditory steady state responses were recorded in response to auditory stimuli delivered over a range of frequencies (10-80 Hz) and averaged over 50 trials. Evoked power was computed under baseline condition and after vehicle or MK-801 (0.03 mg/kg, iv). MK-801 produced a significant attenuation in response to 40 Hz auditory stimuli while entrainment to other frequencies was not affected. Time-frequency analysis revealed deficits in both power and phase-locking to 40 Hz. Nicotine (0.1 mg/kg, iv) administered after MK-801 reversed the attenuation of the 40 Hz response. Administered alone, nicotine augmented 40 Hz steady state power and phase-locking. Nicotine's effects were blocked by simultaneous administration of the α4ß2 antagonist DHßE. Thus we report for the first time, a rodent model that mimics a core neurophysiological deficit seen in patients with schizophrenia and a pharmacological approach to alleviate it.
Subject(s)
Auditory Cortex/drug effects , Brain Waves/drug effects , Dizocilpine Maleate/pharmacology , Nicotine/pharmacology , Acoustic Stimulation , Anesthetics, Intravenous/pharmacology , Animals , Auditory Cortex/physiology , Brain Waves/physiology , Dihydro-beta-Erythroidine/pharmacology , Dizocilpine Maleate/antagonists & inhibitors , Evoked Potentials, Auditory/drug effects , Evoked Potentials, Auditory/physiology , Excitatory Amino Acid Antagonists/pharmacology , Male , Nicotine/antagonists & inhibitors , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Rats , Urethane/pharmacologyABSTRACT
Optical imaging over extended periods of time in non-human primates presents serious challenges because the dura mater must be removed to expose the cortical surface. We present a novel nylon imaging chamber with a transparent artificial dura implant, which allows repeated, long-term optical recordings from the cortex. The cylinder of the chamber is inserted into a cranial trephination and held in place with a minimum of screws and acrylic cement. A round patch of artificial dura with a perpendicular wall protects the cortical surface and slows re-growth of dural tissue within the chamber. A cap, manufactured from the same material as the cylinder, is screwed into the chamber and seals it completely. Over a period of 1-4 months, the chamber required a minimum of maintenance and stayed infection-free without local antibiotic application. We repeatedly performed optical imaging in the same animal with the advantages of shortened preparation time. To permit precise alignment and comparison of maps obtained from different imaging sessions, we developed a program that calculated a 2-dimensional spatial transformation between maps of different magnifications, translations, and distortions. We suggest that these methods provide a practical solution to long-term optical imaging in the anesthetized or alert monkey. The exclusive use of non-metallic materials offers the benefit of a lighter and more compact implant, and the possibility to perform MRI scans after chamber implantation.
