The goal of this project is to develop an understanding of the basic regulatory mechanisms in neurons and endocrine cells which secrete peptides, and through this understanding, develop novel pharmacotherapeutic approaches and agents for manipulating peptidergic neuronal and endocrine systems. Two projects are ongoing. The first studies the regulation of biosynthesis of peptides. The primary model investigated is the neuronal and endocrine opioid system which secretes ACTH, Alpha-MSH and Beta-endorphin- peptides all derived from a commmon prohormone, pro-opiomelanocortin (POMC). Our investigations indicate that regulation of POMC gene expression occurs primarily at the transcriptional level. In addition, there appears to be coordinate regulation of the POMC gene and certain of the processing enzyme genes. The expression of POMC and processing enzyme genes appear to be regulated by cAMP-protein kinase A and diacylglycerol-protein kinase C mediated mechanisms. The second investigation is focused on studies of the phencyclidine (PCP)/sigma opioid receptor and an endogenous ligand, Alpha-endopsychosin, which interacts with these receptors. Alpha-Endopsychosin was isolated from extracts of porcine brain based on the ability of the compound to inhibit the binding of phencyclidine to brain receptors. Structural studies indicate the Alpha-endopsychosin is a peptide 26 amino acids long with a blocked amino terminus. Pharmacological studies of the peptide and PCP/sigma opioid analogues indicate that there are multiple PCP/sigma opioid receptors. Studies using the recently developed PCP acylating agent, Metaphit, also demonstrated that this compound would only antagonize the psycotomimetic effects of certain sigma opioids. Its ability to antagonize the effects of PCP suggest that Metaphit or a structural derivitive may find clinical utility for the treatment of PCP overdose.
