4-PhPr-2,5-DMA

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| class = Serotonin receptor modulator; Serotonin 5-HT_2A receptor partial agonist

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| PubChem = 44265227

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| ChemSpiderID = 23108650

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| ChEMBL = 8334

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| synonyms = 4-(3-Phenylpropyl)-2,5-dimethoxyamphetamine; 2,5-Dimethoxy-4-(3-phenylpropyl)amphetamine; 4-PP-2,5-DMA; DOPP; DOPhPr; DOPh3

| IUPAC_name = 1-[2,5-dimethoxy-4-(3-phenylpropyl)phenyl]propan-2-amine

| C=20 | H=27 | N=1 | O=2

| SMILES = CC(CC1=C(C=C(C(=C1)OC)CCCC2=CC=CC=C2)OC)N

| StdInChI = 1S/C20H27NO2/c1-15(21)12-18-14-19(22-2)17(13-20(18)23-3)11-7-10-16-8-5-4-6-9-16/h4-6,8-9,13-15H,7,10-12,21H2,1-3H3

| StdInChIKey = XKCYCNKOOGOHIQ-UHFFFAOYSA-N

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4-(3-Phenylpropyl)-2,5-dimethoxyamphetamine (DOPP or DOPhPr), also known as 4-PhPr-2,5-DMA, is a serotonin receptor modulator of the phenethylamine, amphetamine, and DOx families.{{cite journal | vauthors = Nichols DE | title=Structure–activity relationships of serotonin 5-HT2A agonists | journal=Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | volume=1 | issue=5 | date=2012 | issn=2190-460X | doi=10.1002/wmts.42 | doi-access=free | pages=559–579 | quote=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}}{{cite book | vauthors = Nichols DE | title = Chemistry and Structure-Activity Relationships of Psychedelics | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = | quote = 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).}}{{cite journal | vauthors = Trachsel D, Nichols DE, Kidd S, Hadorn M, Baumberger F | title = 4-aryl-substituted 2,5-dimethoxyphenethylamines: synthesis and serotonin 5-HT(2A) receptor affinities | journal = Chem Biodivers | volume = 6 | issue = 5 | pages = 692–704 | date = May 2009 | pmid = 19479848 | doi = 10.1002/cbdv.200800235 | url = | quote = 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. }}{{cite journal | vauthors = Glennon RA, Dukat M | title = 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review | journal = ACS Pharmacol Transl Sci | volume = 7 | issue = 6 | pages = 1722–1745 | date = June 2024 | pmid = 38898956 | doi = 10.1021/acsptsci.4c00157 | url = | doi-access = free | pmc = 11184610 }}{{cite journal | vauthors = Glennon RA, Teitler M, Sanders-Bush E | title = Hallucinogens and serotonergic mechanisms | journal = NIDA Res Monogr | volume = 119 | issue = | pages = 131–135 | date = 1992 | pmid = 1435968 | doi = | url = https://archives.nida.nih.gov/sites/default/files/monograph119.pdf#page=161}}{{cite journal | vauthors = Dowd CS, Herrick-Davis K, Egan C, DuPre A, Smith C, Teitler M, Glennon RA | title = 1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT(2A) partial agonists | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 16 | pages = 3074–3084 | date = August 2000 | pmid = 10956215 | doi = 10.1021/jm9906062 | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=ad45346022bb7e6e1bec1fbfbcca3bcb60b13058 | url-access = subscription }} It shows high affinity for both the serotonin 5-HT_2A and 5-HT_2C receptors and acts as a weak partial agonist or antagonist of the serotonin 5-HT_2A receptor. The drug has lower affinity for the serotonin 5-HT_2A receptor than its closely related positional isomer 4-PhPr-3,5-DMA. This is an apparent reversal of the usual situation with DOx and related drugs in which the 2,5-dimethoxy pattern is optimal for serotonin 5-HT_2A receptor interactions.