brainpenetrant

Brainpenetrant describes a chemical compound that is able to cross the blood–brain barrier (BBB) and reach the central nervous system in pharmacologically meaningful concentrations. Brainpenetrant properties are desirable for drugs intended to act in the brain, such as analgesics, antidepressants, antipsychotics, and neuroprotective agents, but unnecessary or undesirable for peripherally acting drugs.

Penetration depends on multiple properties: molecular size, lipophilicity, polar surface area, hydrogen bonding, ionization state at physiological pH, and substrate status for efflux transporters such as P-glycoprotein. Typically, small, moderately lipophilic molecules with limited hydrogen bonding and favorable pKa cross by passive diffusion, while some compounds use carrier-mediated transport systems. Efflux transporters can limit brain exposure by pumping substrates back into the blood.

Assessment commonly uses in vitro and in vivo measures. In vitro models estimate permeability and transporter interactions; in vivo, brain-to-plasma concentration ratios or unbound brain-to-plasma partition coefficients (Kp,uu) are used. Computational approaches, including logBB and CNS MPO scores, aid early prioritization.

Examples of brainpenetrant drugs include many CNS therapeutics such as diazepam and morphine, which reach brain tissue, as well as L-dopa, which uses amino acid transporters. Not all brain-penetrant compounds are effective; high CNS exposure must align with target engagement and safety, as excessive CNS penetration can cause sedation, abuse potential, or neurotoxicity.

As with all drugs, achieving brain penetration involves balancing efficacy, selectivity, and safety, and is a central consideration in CNS drug discovery and toxicology.