The fumarate salts of the N-isopropyl-N-methyl derivatives of DMT and psilocin

The crystal structures of the fumarate salts of the psychomimetics MiPT and 4-HO-MiPT are reported. The extended structure of both compounds feature two-dimensional networks of ions connected through N—H⋯O and O—H⋯O hydrogen bonds.


Chemical context
N,N-dimethyltryptamine (DMT) and its derivatives have been used by humans for centuries because of their psychoactive, entheogenic, or hallucinogenic effects, or combinations thereof (Cameron & Olson, 2018). Psilocybin, the 4-phosphate variant of DMT, is arguably its most studied derivative. Psilocybin is one of several naturally occurring psychoactive tryptamines found in 'magic' mushrooms. When consumed by humans, psilocybin serves as a prodrug of psilocin. Upon digestion, psilocybin hydrolyses to generate psilocin, the 4-hydroxy derivative of DMT. Psilocin is a potent seratonin 2a-agonist, which is responsible for its psychoactive properties (Dinis-Oliveira, 2017;Nichols, 2012). Psychoactive tryptamines like DMT and psilocin have garnered significant interest recently because of their potential for treating mood disorders, including depression, anxiety, addiction, and post-traumatic stress disorder (PTSD) (Johnson & Griffiths, 2017;Carhart-Harris & Goodwin, 2017).
Altering the chemical structure within this class of compounds can dramatically influence the potency and action of the drugs. For example, merely changing the N,N-dialkyl groups on DMT can modify its psychoactive properties: increasing the chain length of the two alkyl groups of the tryptamine to larger than n-butyl dramatically reduces or eliminates the psychoactive effects (Bradley & Johnston, 1970).
The synthesis of N-methyl-N-isopropyltryptamine (MiPT) was reported in 1981 (Repke et al., 1981). In 1985, Repke and co-workers reported that of the compounds in the series of N,N-dialkyl-4-hydroxytryptamines, the N-methyl-N-isopropyl derivative (4-HO-MiPT) is the most potent based upon qualitative effects on humans (Repke et al., 1985). Later quantitative studies showed the N-methyl-N-isopropyl derivatives of DMT and psilocin to be more potent as seratonin-1A, À2A and À2B receptors compared to the analogous dimethyl compounds (McKenna et al., 1990). Improving our understanding of how these drugs interact with particular biological receptors requires a complete understanding of their chemical structures. Given their therapeutic potential and the significant structure-activity relationship between them, further studies would benefit from better understanding of their chemical structures. Responding to this unmet need, we report the crystal structures of the fumarate salts of MiPT and 4-HO-MiPT herein.

Structural commentary
The molecular structure of MiPT fumarate is shown on the left of Fig. 1. The asymmetric unit contains one N-methyl-N-isopropyltryptammonium (C 14 H 21 N 2 + ) cation and one 3-carboxyacrylate (C 4 H 3 O 4 À ) anion. The indole ring system of the cation is near planar with an r.m.s. deviation from planarity of 0.006 Å . The singly protonated fumarate anion is in the trans configuration and is slightly distorted from planarity with an r.m.s. deviation of 0.133 Å and a carboxylate twist angle of 18.370 (5) . The N-methyl-N-isopropylammonium group is disordered over two orientations in a 0.630 (3):0.370 (3) ratio.
The molecular structure of 4-HO-MiPT fumarate monohydrate is shown on the right of Fig. 1. The asymmetric unit contains one 4-hydroxy-N-methyl-N-isopropyltryptammo-nium (C 14 H 21 N 2 O + ) cation, one 3-carboxyacrylate anion and one water molecule of crystallization. The indole ring system of the cation is close to planar with an r.m.s. deviation of 0.021 Å . The singly protonated fumarate anion is also near planar with an r.m.s. deviation of 0.049 Å . The N-methyl-Nisopropylammonium group shows a similar disorder to the MiPT structure over two orientations in a 0.775 (5):0.225 (5) ratio.

Supramolecular features
In the extended structure of MiPT fumarate, the N-methyl-Nisopropylamine and fumarate ions are linked into infinite twodimensional networks lying parallel to the (010) plane through N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds (Table 1). The proton of the ammonium cation forms a hydrogen bond with one of the oxygen atoms of the deprotonated -CO 2 À group of the 3-carboxyacrylate ion. The carboxylic acid proton forms a hydrogen bond with an oxygen atom of an adjacent 3-carboxyacrylate anion. The N-H grouping of the indole ring also hydrogen bonds to one of the oxygen atoms of the 3-carboxyacrylate anion. The hydrogen bonding is shown on the left in Fig. 2, and the packing of MiPT fumarate is shown on the left in Fig. 3.

Figure 2
The hydrogen bonding of the fumarate ion in the structure of MiPT (left) and HO-MiPT (right). Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms not involved in hydrogen bonds are omitted for clarity. Only one component of the amine disorder is shown. Symmetry codes: the deprotonated -CO 2 À group of the 3-carboxyacrylate ion. The hydrogen of the hydroxy group also hydrogen bonds to the same oxygen atom of the anion. The carboxylic acid proton hydrogen bonds with a water molecule in the structure. Two other water molecules form hydrogen bonds with two different oxygen atoms of the anion. The hydrogen bonding is shown on the right in Fig. 2, and the packing of 4-HO-MiPT fumarate is shown on the right in Fig. 3.

Database survey
The MiPT structure described above is a derivative of DMT (N,N-dimethyltryptamine), which has been structurally characterized (Falkenberg, 1972), as well as its close derivative MPT, N-methyl-N-propyltryptamine (Chadeayne et al. 2019b). In both cases, these were crystallized as free bases, while MiPT is the fumarate salt. In the case of 4-HO-MiPT, the most closely related molecule is psilocin, which has been structurally characterized , as well as psilocybin . Psilocin was reported as the free base and psilocybin was reported as a zwitterionic molecule, while the structure of 4-HO-MiPT reported here is the hydrated fumarate salt. Two different ionic structures of the 4-acetoxy derivative of DMT have been reported as  Table 2 Hydrogen-bond geometry (Å , ) for 4-HO-MiPT.  (2) 170 (2) Symmetry codes: (i) Àx þ 3 2 ; Ày þ 1 2 ; Àz þ 1; (ii) Àx þ 1; Ày þ 2; Àz; (iii) x; y þ 1; z.

Figure 3
The crystal packing of MiPT fumarate (left), viewed along the a axis, and the crystal packing of HO-MiPT fumarate (right), viewed along the b axis. The hydrogen bonds (Tables 1 and 2)

Synthesis and crystallization
Single crystals suitable for X-ray analysis were obtained from the slow evaporation of aqueous solutions of commercial samples of N-methyl-N-isopropyltryptammonium fumarate and 4-hydroxy-N-methyl-N-isopropyltryptammonium fumarate (The Indole Shop).

[2-(1H-Indol-3-yl)ethyl](methyl)propan-2-ylazanium 3-carboxyprop-2-enoate (MiPT)
Crystal data  Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )

MiPT)
Crystal data

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.