Design in topographical space of peptide and peptidomimetic ligands that affect behavior. A chemist's glimpse at the mind--body problem.

Efforts to determine the bioactive conformations of peptide ligands for membrane-bound proteins such as G-protein-coupled receptors (GPCRs) have been particularly challenging due to the flexibility of the ligands and the lack of 3D structural information (X-ray, NMR, etc.) for integral membrane proteins. An approach to determining these conformations by conformational constraint of the backbone template (phi and psi angles) and by topographical constraint (chi(1), chi(2), etc. constraint) is outlined. Special attention is given to peptide neurotransmitter ligands that affect critical behaviors (feeding, sexual, addiction, pain, etc.). It is demonstrated that small changes in structure or a single torsional angle are sufficient to dramatically modify complex behaviors.