A common structural model for central nervous system drugs and their receptors

On the basis of the hypothesis that there is a common structural basis for central nervous system (CNS) drug action consisting primarily of an aromatic group and a nitrogen atom, a four-point model for a common pharmacophore is defined with use of five semirigid CNS-active drug molecules: morphine, strychnine, LSD, apomorphine, and mianserin. Two of the points of the model represent possible hydrophobic interactions between the aromatic group and the receptor, while the other two represent hydrogen bonding between the nitrogen atom and the receptor. The model is then extended by the inclusion of nine additional CNS-active drug molecules: phenobarbitone, clonidine, diazepam, bicuculline, diphenylhydantoin, amphetamine, imipramine, chlorpromazine, and procyclidine, each being chosen as a key representative of a different CNS-active drug class or neurotransmitter system. Consideration of all phenyl group and nitrogen atom combinations, as well as all feasible conformations, shows that all nine molecules closely fit the common model in low-energy conformations. It is proposed that the model may eventually be used to design CNS-active drugs by mapping the relative locations of secondary binding sites. It can also be used to predict whether a given structure is likely to show CNS activity: a search over 1000 entries in the Merck Index shows a high probability of CNS activity in compounds fitting the common structural model.