For nearly 80 years, only two neuropeptides were known that exhibited any important biological activity (oxytocin and vasopressin). In the past 20 years, over 50 other peptides have been identified and characterized that have pharmacological functions ranging from that of neurotransmitter or neuromodulator to circulatory hormone. The amino acid sequences of these hormones have been elucidated. We are interested in the solid phase peptide synthesis of conformationally designed analogs of the alpha, beta, and gamma- melanocyte stimulating hormones (alpha-, beta, gamma- MSH). The MSHs are known to have numerous actions with regard to effects in the endocrine and central nervous system (CNS). These effects include: 1) mediation of melanin synthesis;2) learning and memory behavior, affecting attentional processes;3) acting as a modulator for release of other hormones, e.g., the growth hormone;4) placental development and fetal growth; 5) sexual behavior, such as arousal;6) aggressive behavior, such as increase submission, tendency to avoid attack and abolition of aggression;7) analgesia activity, including morphine induced analgesia activity, including morphine induced, analgesia. The goal of our work is to design biologically active analogs that have little hormology to the sequences of the naturally occurring peptide. This strategy is based on the thesis that an amphophilic secondary structure is the dominant factor determining the receptor binding characteristics and transduction. The structure-activity studies of this work can add fundamental knowledge to the mechanism of action of this hormonal system. The analogs may test to have use in the treatment of learning disorders and to the treatment of human and animal central nervous system endocrine diseases.
