5-MeO-pip-T was described and partiallysynthesized byAlexander Shulgin in his 1997 bookTiHKAL (Tryptamines I Have Known and Loved), but he did not test it or define its properties or effects.[1] According to Shulgin, he was not in a hurry to test it owing to the unfavorable effects of thestructurally related5-MeO-pyr-T.[1]
^abcdefgShulgin A,Shulgin A (September 1997).TiHKAL: The Continuation.Berkeley, California:Transform Press.ISBN0-9630096-9-9.OCLC38503252. "With both pyr-T and 4-HO-pyr-T, there are two additional ring analogies that are natural companions to 5-MeO-pyr-T. These are the piperidine and the morpholine counterparts, 5-MeO-mor-T and 5-MeO-pip-T. Both compounds are in the literature, and an entry reference to them can be gotten from the “known tryptamines” appendix. [...] With the rather unexpected, and unencouraging descriptions of the pyrrolidine tryptamines in general, and this one in particular, I was not too blinding a hurry to explore the two heterocyclic analogues. The amides are still on the shelf in the lab. If some good reason comes forth to assay the final amines, they can be made with a dash of lithium aluminum hydride, but until then I have other things to do."
^abcdGlennon RA, Dukat M, el-Bermawy M, Law H, De los Angeles J, Teitler M, et al. (June 1994). "Influence of amine substituents on 5-HT2A versus 5-HT2C binding of phenylalkyl- and indolylalkylamines".Journal of Medicinal Chemistry.37 (13):1929–1935.doi:10.1021/jm00039a004.PMID8027974.
^abcdWarren AL, Lankri D, Cunningham MJ, Serrano IC, Parise LF, Kruegel AC, et al. (June 2024). "Structural pharmacology and therapeutic potential of 5-methoxytryptamines".Nature.630 (8015):237–246.Bibcode:2024Natur.630..237W.doi:10.1038/s41586-024-07403-2.PMID38720072.Extension of the methyl groups of 5-MeO-DMT (Gi BRET half-maximum effective concentration (EC50) = 25.6 nM) to one ethyl group (5-MeO-MET; Gi BRET EC50 = 25.9 nM) or two ethyl groups (5-MeO-DET; Gi BRET EC50 = 37.1 nM) only marginally affected 5-HT1A potency while retaining full efficacy, with similarly small effects at 5-HT2A (Supplementary Table 1). By contrast, a cyclic pyrrolidine substituent increased potency at 5-HT1A by about 12-fold (5-MeO-PyrT; Gi BRET EC50 = 2.1 nM) and decreased 5-HT2A potency by about 3-fold relative to 5-MeO-DMT. Cyclization of the amine moiety alone resulted in an approximately 38-fold increase in 5-HT1A > 5-HT2A selectivity. Next, we modestly decreased the steric demand of the pyrrolidine by removing two C-H bonds and installing a π bond. This change led to a further increase of around eightfold in potency at 5-HT1A (5-MeO-3-PyrrolineT; Gi BRET EC50 = 0.3 nM). By contrast, increasing the ring size to a six-membered piperidine (5-MeO-PipT; Gi BRET EC50 = 88.5 nM) led to an approximate 42-fold loss of potency relative to 5-MeO-PyrT, which indicated a sensitivity to steric bulk at 5-HT1A (Fig. 2b). [...]
