Chronic clinical pain remains poorly treated. The use of mu opioid analgesics is effective in treating chronic pain, but the rapid development of tolerance to the analgesic effects necessitates ever increasing doses to be administered. However, tolerance to the constipatory effects occurs at a slower rate, a condition we refer to as differential tolerance. There is a great need to develop opioids to which differential tolerance does not develop in order to reduce the severity of constipation. Our hypothesis is that the efflux transporter, P-glycoprotein (P-gp), contributes to the development of central tolerance by actively pumping morphine out of the CNS. P-gp is present at the BBB, morphine is a known P-gp substrate, and P-gp is up-regulated in morphine and oxycodone tolerant animals. As analgesia is primarily central and constipation is primarily peripheral, up-regulation of P-gp would be expected to lead to lower brain concentrations of morphine compared to naive animals; therefore, contributing to tolerance. The design of opioids with decreased activity as P-gp substrates is anticipated to produce analgesics with reduced differential tolerance and therefore, diminished constipation. Meperidine, a moderately potent mu opioid receptor agonist causes less constipation than morphine clinically and has lower P-gp substrate activity than morphine. We have worked towards the optimization of meperidine by (1) employing opioid N-substituent SAR to increase its potency similar to morphine, (2) synthesizing isosteric replacements of the 4-ester to increase duration of action, and (3) introducing steric hinderance into the piperidine ring at the 2- and 6-positions to eliminate toxic metabolite formation. All analogs were analyzed for opioid receptor binding and P-gp substrate affinity. Results showed the optimal N-substituent was N-methyl; the ester was superior in the 4-position, and the introduction of a m-OH into the phenyl ring increased P-gp substrate affinity. Progress towards introducing steric hindrance is reported along with the strategy for their completion. Additional work on the synthesis and development of (1) selective sigma-1 ligands for stimulant abuse; and (2) a dual profile inhibitor of the S100beta and p53 interaction involved in malignant melanoma is presented.