This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The main goal of this project is to continue developing novel organic synthetic methodology for the preparation of potential nicotinic receptor agonist that will be valuable for the treatment of neuron-degenerative diseases, such Alzheimer and Parkinson, schizophrenia, attention deficit/hyperactivity and Tourette's syndrome and in the treatment of nicotine addition. In general, our work will focus on four major research areas: 1) development of new methodology for the asymmetric synthesis of biological important pyridyl and heterocyclic amino derivatives using our recently developed spiroborate catalysts for the reduction of ketones and oxime ethers;2) design and synthesized novel chiral nicotinic analogs and of chiral drugs for neurodegenerative diseases;3) biological testing of the new synthesized compounds as nicotinic receptor agonist, acetyl cholinesterase inhibitors and possibly, with antioxidant properties carried out in Dr. Lasalde Neurobiology Laboratory at UPR, Biology Department;and 4) study the structural factors affecting the reactivity and stereochemistry of the catalysts in the proposed synthetic methodology, in addition to the structure-activity studies that will be addressed by the CoPI, Dr. Carmelo Garcia, from UPR-Humacao using Gaussian 03 or Spartan 2.0 chemical computational methods. The results on this proposed interdisciplinary project on the search for new method for potential new nAChRs agonist are expected to strengthen our research capability for the submission of an RO1 proposal.
Specific Aims : 1) To investigate the borane-mediated reduction of prochiral multifunctional ketones and oximes using spiroborate reagents and study their transformation to more complex chiral amino ethers, amino alcohols and diamino compounds. 2) To explored the use of spiroborate ester catalyst for the asymmetric reduction of model A/-substitute imines. 3) To establish protocols for the synthesis of novel alcohols and amino derivatives as nicotinic receptor agonist with multifunctional neuronal functions. 4) To test the new amino compounds as potential agonists for neuronal nicotinic receptors (nAChRs) and cholinesterase inhibitors using voltage clamp techniques and recombinant expression of nAChRs in oocytes and its electrophysiological characterization at mice neuromuscular junction. 5) To establish the optimal stereochemistry of chiral reagents and transition states for the proposed enantioselective reactions using molecular modeling methods. Molecular modeling will also be used to study the correlation between agonist's structure and observed and calculated affinities for the nACH receptors.
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