Part A. N-methyl-D-aspartate (NMDA) receptors located on neurons have potential therapeutic value since they are involved in acute and chronic neurodegeneration. Associated with the NMDA receptor is a channel governing the flow of Ca²⁺, K⁺, and other ions in neuronal cells. Over-stimulation of neurons during states of ischaemia, such as stroke, can cause death of such neurons by allowing too much Ca ²⁺ into neurons. NMDA receptor antagonists have potential as neuroprotective agents by blocking this ion channel. Quantitavite Structure-Activity Relationship (QSAR) studies were performed based on the phencyclidine (PCP) analogs reported in literature. The designed agents, PCP analogs, are expected to bind inside of and block the cation channels associated with NMDA receptors, preventing further firing of the neurons even in the presence of excitants. The purpose of this study was to synthesize novel compounds designed as noncompetitive NMDA receptor antagonists. All of the target compounds were synthesized in four steps, and the net yields varied from 5 to 60%. Tertiary alcohols were synthesized from required Grignard reagents and norcamphor or cycloheptanone. These alcohols reacted with sodium azide in the presence of tnfluoroacetic acid to lead to tertiary azides. Lithium aluminum hydride reduced these azides to the corresponding amines. Treatment of the amines with 1, 5-dibromopentane or 1, 4-dibromobutane in the presence of potassium carbonate led to the target compounds. Each compound was characterized by obtaining ¹H, ¹³C, and ¹⁹F-NMR spectra as well as MS, all of which were consistent with proposed structures. Pharmacological evaluations of the compounds in mice and rats showed that compounds (±) 2-(4-fluorophenyl)bicyclo[2.2.1]heptan-2-amine (119b), (±)1-(2-(3-fluorophenyl)bicyclo[2.2.1]heptan-2-yl)piperidine (119d), 1-(4-fluorophenyl)cycloheptanamine (120a) and 1-(1-(4-fluorophenyl)cycloheptyl)piperidine (120d) had anticonvulsant activities in mice at 100 mg/kg, but 119b, 120a and 120d also showed toxicity at a higher dose of 300 mg/kg. Compound 119d showed much less toxicity than the other compounds and had oral activity. The side effects of this compound are tremors and hyperactivity at high doses. The oral ED₅₀ of compound 119d fumarate is 28.33 mg/kg in the rat MES model. The K_i of compound 119d fumarate on the NMDA receptor was 9.55 * 10^-6 M, and IC₅₀ of it was 1.31 * 10^-5 M. The IC₅₀ values of compound 119d fumarate are 9.09 * 10 ^-6 M on sigma 1 and 4.98 * 10^-6 M on sigma 2 receptors. The physicochemical property studies showed that compound 119d bore good characteristics. The log P value is estimated to be 2.07. The pKa value is 8.87. The intrinsic solubility and aqueous solubility of 119d fumarate are 0.0366 M and 23.0 mg/ml respectively. The RM value of 119d is 2.16. Further pharmacological evaluations of compound 119d are ongoing.

Part B. Drug targeting to the colon is an important method to provide localized treatment of colon diseases. Many currently available drugs to treat Crolm's disease and ulcerative colitis are absorbed, at least partially, from the small intestine upon oral administration, resulting in the drug entering the systemic circulation. Unfortunately, such drugs in systematic circulation can cause more side effects than therapeutic benefits. Chitosan is a biodegradable polymer which has demonstrated the potential for use in targeted delivery to the colon. The purpose of this study was to design and synthesize chitosan-drug conjugates for colon-specific drug delivery.

For the current study, 5-aminosalicylic acid served as a model drug. The conjugate was designed so that appropriate enzymes found in the colon could cleave desired bonds and release the drug under conditions mimicking the colonic environment. Reaction of chitosan with protected sulfonyl chloride gave the corresponding sulfonamide. Deprotection followed by generation of the corresponding azide using nitrous acid, and reaction with salicylic acid generated the desired conjugates. In the chemical process, reactions were carried out using 2 different molecular weight chitosan samples. The net yield of each of the conjugates was over 80%. The intermediates and final products were characterized by NMR, DSC and IR. The feasibility of this scheme was verified by using a small molecule model.