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 (φ and ψ angles) and by topographical constraint (χ¹, χ², 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.