A fundamental understanding of the relationship between structure and activity of neurotransmitters in the human brain is of vital importance for the design targeted drugs. Using density functional theory and hybrid exchange correlation energy functionals we have studied the structure-activity-relationships of some important neurotransmitters and selected drugs by calculating their absolute hardness (η) and absolute electronegativity (χ). A plot of the η- χ diagram allowed us to assign them into three distinct groups, namely, (i) Acetylcholine analogs (positively charged structure), (ii) GABA analogs (zwitterionic structures) and (iii) monoamines. The results suggest that brain stem is chemically soft because of distribution of monoaminergic nerve pathways. Prefrontal cortex is also chemically soft due to secretion of dopamine from mesocortical dopaminergic nerve A10, whereas neocortex is chemically hard due to presence of zwitterionic neurotransmitters. Target drugs (agonists/antagonists) can also be predicted by comparing the η- χ diagram of neurotransmitters with those of the drugs
