RGFP966

Pharmacodynamics

RGFP966 is a histone deacetylase (HDAC) inhibitor, specifically acting as a highly selective HDAC3 inhibitor, with an IC₅₀Tooltip half-maximal inhibitory concentration of 80 nM and no inhibition of other HDACs at concentrations of up to 15,000 nM or 20,000 nM.^[2][3][4]

It enhances cognition, memory, and learning in rodents.^{[2][6][9][10][11][12][13][14]} The drug reverses age-related impairments in memory updating in rodents.^[14] In addition, it has been found to facilitate the extinction of drug-seeking behavior in a manner refractory to reinstatement in rodents.^[2][15] Conversely, unlike the pan-class I HDAC inhibitor RGFP963, RGFP966 failed to enhance consolidation of cued fear extinction in rodents, suggesting that HDAC1 and/or HDAC2 may be involved in this instead.^[4]

Also unlike pan-class I HDAC inhibitors, which can enhance synaptogenesis, RGFP966 showed minimal effect in this regard.^[6] The drug increases brain-derived neurotrophic factor (BDNF) expression.^[13][16] Knockdown of HDAC2 and knockdown of HDAC3 have been found to increase BDNF expression, whereas knockdown of other HDACs did not do so.^[13]

RGFP966 produces anti-inflammatory effects.^{[8][17][18][19][20][3][21]} It shows antidepressant-like effects against neuroinflammation-induced depression in rodents.^[3] Similarly to butyric acid (butyrate), RGFP966 ameliorates sleep deprivation-induced intestinal mucosa-induced damage in rodents.^[22] RGFP966 has neuroprotective^{[19][23][24][25]} and neurorestorative effects in preclinical research.^[26][27]

Pharmacokinetics

The pharmacokinetics of RGFP966 in rodents have been described.^[2] It efficiently crosses the blood–brain barrier in rodents.^[2]