Chemistry:4-PhPr-3,5-DMA

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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.[1] 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.[1]

The affinities (Ki) of 4-PhPr-3,5-DMA for the serotonin 5-HT2 receptors have been reported to be 4 nM for the serotonin 5-HT2A receptor and 40 nM for the serotonin 5-HT2C receptor, with approximately 10-fold selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor.[1] Its affinities for the serotonin 5-HT2A and 5-HT2C receptors in the study were approximately 8-fold and 1.6-fold higher than those of DOB, respectively.[1] The drug was a full agonist of the serotonin 5-HT2A receptor in terms of phosphatidylinositol (PI) hydrolysis (Emax = 109% relative to serotonin).[1] However, in the presence of the serotonin 5-HT2A receptor silent antagonist ketanserin, which should have abolished stimulation, 4-PhPr-3,5-DMA still produced 43% activation of PI hydrolysis.[1] These findings suggest that 4-PhPr-3,5-DMA may be acting in the assay via a combination of both serotonin 5-HT2A receptor partial agonism and another unknown ketanserin-insensitive mechanism.[1]

The observed serotonin 5-HT2A 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-HT2A receptor.[1] 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.[1] The study's findings suggest that bulky substitutions at the 4 position of DOx-like amphetamines can provide enhanced serotonin 5-HT2A receptor affinity but will not inevitably result in antagonism.[1] Instead, agonism, and possible psychedelic effects, may be retainable with specific substitution patterns.[1]

An analogue is 4-PhPr-2,5-DMA (DOPP or DOPhPr), which is also a weak partial agonist of the serotonin 5-HT2A receptor.[2][3][4][1]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 "1-[4-(3-Phenylalkyl)phenyl-2-aminopropanes as 5-HT(2A) partial agonists"]. Journal of Medicinal Chemistry 43 (16): 3074–3084. August 2000. doi:10.1021/jm9906062. PMID 10956215. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=ad45346022bb7e6e1bec1fbfbcca3bcb60b13058. 
  2. ↑ "Structure–activity relationships of serotonin 5-HT2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1 (5): 559–579. 2012. doi:10.1002/wmts.42. ISSN 2190-460X. "Very large bulky groups at the 4-position, such as the tert-butyl, lead to inactive compounds,16,71–74 although the 4-isopropyl compound DOIPr is reported to retain good human activity.16 Not surprisingly, therefore, aryl groups attached at the 4-position gave antagonists, generally with low affinity.75 Interestingly, however, when a 3-phenylpropyl substituent was introduced at this position, the compound proved to be a weak partial agonist.76". 
  3. ↑ Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. 36. 2018. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. "Large bulky alkyl groups at the 4-position, such as isopropyl or tert-butyl, lead to inactive compounds (Glennon et al. 1981, 1982a; Glennon and Rosecrans 1982; Oberlender et al. 1984). Not surprisingly, therefore, aryl groups attached at the 4-position also gave antagonists, generally with low affinity (Trachsel et al. 2009). Interestingly, however, when a 3-phenylpropyl substituent was introduced at this position, the compound was reported to be a weak partial agonist (Dowd et al. 2000)." 
  4. ↑ "4-aryl-substituted 2,5-dimethoxyphenethylamines: synthesis and serotonin 5-HT(2A) receptor affinities". Chem Biodivers 6 (5): 692–704. May 2009. doi:10.1002/cbdv.200800235. PMID 19479848. "Usually, compounds of structure 2 bearing a small lipophilic substituent at the crucially important 4’-position possess agonist behavior (Y¼halogen, Me, CF3 , etc.), whereas those having a large lipophilic substituent (Y¼alkyl chainC4 , 3-phenylpropyl, etc.) have antagonist activity [11], but to date the transition between these structures is not well-defined. [...] One may argue that a simple 4’-phenyl substituent in 2-phenylethylamines is still not large enough to allow full interaction with an 'antagonistic binding site' in the 5- HT2A receptor, and that its steric bulk exceeds a limited space in the agonistic binding site. As soon as a further substituent is introduced, (especially) in the para-position of the second arene moiety, antagonistic binding increases dramatically, a conclusion that completely agrees with the results of Glennon and co-workers [11] [32]: i.e., as soon as larger 4’-alkyl or 4’-arylalkyl substituents are introduced into 2-phenylethylamines, the compounds behave as antagonists. [...] Until recently, it was thought that the 2’,5’-(MeO)2 pattern was required for high affinity of phenethylamines at the serotonin 5-HT2A receptor (reviewed in [11]). Although this pharmacophore may be necessary for agonist action, assumed to be the primary pharmacology of hallucinogenic phenethylamines [36] [37], Glennon and coworkers [11] [32] have shown that this substitution pattern is not required for high-affinity antagonists such as 13–15. [...] Fig. 2. Influence of structural modifications upon binding affinities towards 5-HT2 receptors (unless otherwise indicated, Ki values were taken from [11] and [32]). a) Values taken from [2]. The values given in parentheses are more recent [11]; nevertheless, the prior Ki values were used for a consistent comparison. b) This work.". 



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