Multifunctional Receptor-Directed Drugs for Disorders of the Central Nervous System

Jerry J Buccafusco

The marked decline in FDA-approved new drug candidates in recent years suggests the possibility that the "low-hanging fruit" has been almost entirely harvested. This might be particularly applicable to drugs acting on the central nervous system. Fortunately, there are several examples extant for the utility of multifunctional drugs, compounds, or drug mixtures that act on multiple additive or synergistic targets. However, to exploit this approach may require the willingness to consider the possibility that drug targets might be addressed by molecules of rather low specificity and moderate potency. The expectation is that single target molecules with high specificity might not have access to complex interacting neural pathways, and that moderate potency could engender fewer off-target side effects. Though novel compounds might be developed by combining the active functional groups of two or more drug molecules, the approach still lends itself to high throughput screening of large chemical libraries. Multifunctional compounds might be designed with the ability to: 1) offer both palliative and disease modifying actions, 2) act on targets that produce additive or synergistic therapeutic responses, 3) simultaneously evoke a therapeutic response at the desired target and prevent an undesired response mediated by an alternate target, 4) allow one component to promote the drugable characteristics (e.g., brain penetration) of the therapeutic component, and 5) prolong the duration of effectiveness of one compound by contributing the pharmacodynamic actions of another. The author takes the liberty to include examples of the situations just mentioned from studies in his laboratory in the following discussion.