Effects of 4-position substitutions of diphenidine on blood-brain barrier penetration and dopamine release in the nucleus accumbens of rats.
Forensic toxicology July 1, 2026 Yuta Takahashi, Katsuhiro Okuda, Kazuo Matsubara et al.
Diphenidine (DPD) and its analogues 4-methoxydiphenidine (4MeO-DPD) and 4-hydroxydiphenidine (4OH-DPD) all penetrate the blood-brain barrier and trigger dopamine release in rats. 4OH-DPD produced the highest brain concentrations and dopamine release. Pretreatment with verapamil, a P-glycoprotein inhibitor, increased brain levels and prolonged elimination of all compounds, especially 4MeO-DPD, indicating that P-glycoprotein normally restricts their brain entry. Diphenhydramine, an organic cation transporter inhibitor, had no effect. The findings suggest that P-glycoprotein activity is a key factor in the toxicological risk of these emerging novel psychoactive substances.