4-PhPr-3,5-DMA, also known as 4-(3-phenylpropyl)-3,5-dimethoxyamphetamine, is a serotonin receptor modulator of the phenethylamine and amphetamine families. It is structurally related to the DOx drugs but has one of its methoxy groups in the 3 position instead of 2 position on the phenyl ring and has a bulky substitution at the 4 position of the phenyl ring.
The affinities (K<sub>i</sub>) of 4-PhPr-3,5-DMA for the serotonin 5-HT<sub>2</sub> receptors have been reported to be 4nM for the serotonin 5-HT<sub>2A</sub> receptor and 40nM for the serotonin 5-HT<sub>2C</sub> receptor, with approximately 10-fold selectivity for the serotonin 5-HT<sub>2A</sub> receptor over the serotonin 5-HT<sub>2C</sub> receptor. Its affinities for the serotonin 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors in the study were approximately 8-fold and 1.6-fold higher than those of DOB, respectively. The drug was a full agonist of the serotonin 5-HT<sub>2A</sub> receptor in terms of phosphatidylinositol (PI) hydrolysis ( = 109% relative to serotonin). However, in the presence of the serotonin 5-HT<sub>2A</sub> receptor silent antagonist ketanserin, which should have abolished stimulation, 4-PhPr-3,5-DMA still produced 43% activation of PI hydrolysis. These findings suggest that 4-PhPr-3,5-DMA may be acting in the assay via a combination of both serotonin 5-HT<sub>2A</sub> receptor partial agonism and another unknown ketanserin-insensitive mechanism.
The observed serotonin 5-HT<sub>2A</sub> receptor agonist activity of 4-PhPr-3,5-DMA was surprising, as previously studied DOx derivatives with bulky 4-position substituents such as DOHx had consistently acted as antagonists of the serotonin 5-HT<sub>2A</sub> receptor. In addition, the 3,5-dimethoxy substitution pattern being optimal in the study was unexpected, as the 2,5-dimethoxy pattern has been found to be optimal in the DOx drugs. The study's findings suggest that bulky substitutions at the 4 position of DOx-like amphetamines can provide enhanced serotonin 5-HT<sub>2A</sub> receptor affinity but will not inevitably result in antagonism. Instead, agonism, and possible psychedelic effects, may be retainable with specific substitution patterns.
An analogue is 4-PhPr-2,5-DMA (DOPP or DOPhPr), which is also a weak partial agonist of the serotonin 5-HT<sub>2A</sub> receptor.