Information transfer (transduction) in biological systems by hormones, neurotransmitters, growth factors, etc., are central to maintenance of homeostasis in multicellular life. These biochemical processes require specific molecular recognition and information transduction which modulates cellular function at all levels of expression. We are interested in the physical-chemical basis for intercellular communication and transduction. Our basic hypothesis is that these processes involve specific three-dimensional and dynamic properties of these compounds. To examine this hypothesis, we are developing approaches to the design, synthesis, and biochemical and biophysical evaluation of derivatives and analogues which will have highly specific properties at receptors and unique biological activities, and to examining the interrelationships of ligand and receptor structures to biological function at various levels.
Of particular interest to us are peptide hormones and neurotransmitters and their receptors which control critical aspects of biological function including: (1) Linear and cyclic melanotropins with superpotency (10-100 times the native hormone or neurotransmitter) and receptor selectivity in vitro and in vivo to examine pigmentation, obesity, cardiovascular function, pain, sexual function, etc. (2) Linear and cyclic enkephalins, deltorphins, and other opioids that are highly receptor-specific for controlling pain and addiction. (3) bivalent and trivalent ligands which interact as agonists and antagonists at receptors for treatment of neuropathic and other prolonged pain states; (4) New insights into the mechanisms of normal and pathological states are being sought using our novel ligands; (5) Homomeric and heteromultimeric multivalent ligands for addiction and for treatment of cancer.
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Yamamoto, T., P. Nair, P. Davis, S-W. Ma, E. Navratilova, S. Moye, S. Tumati, J. Lai, T.W. Vanderah, H.I. Yamamura, F. Porreca, and V.J. Hruby. 2007. Design, synthesis and biological evaluation of novel bifunctional C-terminal modified for delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists. Journal of Medicinal Chemistry 50: 2779-2786.
Handl, H.L., R. Sankaranarayanan, J. Josan, J. Vagner, E.A. Mash, R.J. Gillies, and V.J. Hruby. 2007. Synthesis and evaluation of bivalent NDP-alpha-MSH(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R). Bioconjugate Chemistry 18: 1101-1109.
Agnes, R.S., Y.S. Lee, P. Davis, S.W. Ma, H. Badghisi, F. Porreca, J. Lai, and V.J. Hruby. 2006. Structure-activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. Journal of Medicinal Chemistry 49: 2868-2875.
Mayorov, A.V., M. Cai, K.B. Chandler, R.R. Petrov, A.R. Van Scoy, Z. Yu, D.K. Tanaka, D. Trivedi, and V.J. Hruby. 2006. Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. Journal of Medicinal Chemistry 49: 1946-1952.
Handl, H.L., J. Vagner, H. Han, E. Mash, V.J. Hruby, and R.J. Gillies. 2004. Hitting multiple targets with multimeric ligands. Expert Opinion on Therapeutic Targets 8: 565-586.
Alves, I.D., K.A. Ciano, V. Boguslavsky, E. Varga, Z. Salamon, H.I. Yamamura, V.J. Hruby, and G. Tollin. 2004. Selectivity, cooperativity, and reciprocity in the interactions between the delta-opioid receptor, its ligands, and G-proteins. Journal of Biological Chemistry 279: 44673-44682.
Cai, M., M. Stankova, S.J.K. Pond, A.V. Mayorov, J.W. Perry, H.I. Yamamura, D. Trivedi, and V.J. Hruby. 2004. Real time differentiation of G-protein coupled receptor (GPCR) agonist and antagonist by two photon fluorescence laser microscopy. Journal of the American Chemical Society 126: 7160-7161.
Ying, J., K.E. Kover, X. Gu, G. Han, D.B. Trivedi, M.J. Kavarana, and V.J. Hruby. 2003. Solution structures of cyclic melanocortin agonists and antagonists by NMR. Biopolymers 71: 696-716.
Alves, I.D., Z. Salamon, E. Varga, H.I. Yamamura, G. Tollin, and V.J. Hruby. 2003. Direct observation of G-protein binding to the human delta-opioid receptor using plasmon-waveguide resonance spectroscopy. Journal of Biological Chemistry 278: 48890-48897.
Hruby, V.J. 2003. Peptide science: Exploring the use of chemical principles and interdisciplinary collaboration for understanding life processes. Journal of Medicinal Chemistry 46: 4215-4231.
Hruby, V.J. 2002. Designing peptide receptor agonists and antagonists. Nature Reviews Drug Discovery 1: 847-858.
