Synthesis and Biological Analysis of Iso-dimethyltryptamines in a Model of Light-Induced Retinal Degeneration

Abstract

Iso-dimethyltryptamine (isoDMT) analogues with heterocyclic substitutions at the indole C(3) were prepared in a hydrogen autotransfer alkylation and tested in combination with natural and unnatural clavine alkaloids in a model of light-induced retinal degeneration for protection against retinal degeneration. On the basis of measurements with optical coherence tomography and electroretinography, three compounds showed better efficacy than the positive control bromocriptine at equivalent systemically administered doses. These studies provide further insights into the role of serotonin receptors and their potential therapeutic applications in ocular diseases.

Figure 1

Serotonin (5-HT) synthesis and uptake in retina cells (created with BioRender).

Figure 2

Mechanistic hypothesis for the neuroprotective effects of 5-HT_1AR agonists. Cyclic adenosine monophosphate (cAMP) levels are elevated during retinal disease and are driving further degeneration. For instance, cAMP-activated PKA-mediated protein phosphorylation reduces GABA release, thereby causing hyperexcitability associated with glaucomatous damage. Agonists at 5-HT_1A inhibit this cascade by exchanging GDP for GTP on the α-subunit of Gi/o (Giα/Goα), thereby inhibiting adenylyl cyclase (AC) and resulting in decreased cAMP (created with BioRender).

Figure 3

Examples of tryptamines, isoDMTs, and novel 3-methylpyridyl isoDMT analogues.

Scheme 1. Synthesis of isoDMT Analogues by a Hydrogen Autotransfer (HA) Process Followed by N-Alkylation

Figure 4

IsoDMT and clavine alkaloids selected for LIRD analysis.

Figure 5

Systemically administered (+)-lysergol, (+)-isolysergol, and compound 18 display strong protection against LIRD-associated photoreceptor death. (A) Representative OCT images from each study group. Imaging was centered at the optic nerve head (ONH). ONL thickness was measured at 500 μm distance from the ONH border. Panels (B–F) display ONL thickness measurements (data averaged from superior, inferior, nasal, and temporal retinal quadrants) from experiments with lysergols (B), isolysergols (C), cycloclavines (D), 19 and 20 (E), and 18 and 28 (F) all contrasted with the data obtained from vehicle- and positive control (bromocriptine) treatments or baseline conditions (i.e., BALB/c mouse retinas without LIRD). The statistical analysis was performed using the nonparametric Kruskal–Wallis (K–W) test followed by Dunn’s tests for multiple comparisons. The asterisks signify results from the Dunn’s tests: *P < 0.05, ***P < 0.001, and ***P < 0.0001. Data is presented as mean ± SEM.

Figure 6

Retinal protection by (+)-lysergol, (+)-isolysergol, and 18 leads to near normal ERG responses 7 days after LIRD induction. For clarity, this figure presents ERG data from only 1 of 12 stimulation intensities used (10 cd·s/m²); full stimulus intensity–amplitude graphs are presented in Supplementary Figure 4. Panel (A) shows group-averaged ERG waveforms from all study groups. Panels (B–F) and (G–K) display ERG a- (B–F) and b-wave (G–K) amplitudes, respectively, from experiments with lysergols (B,G), isolysergols (C,H), cycloclavines (D,I), 19 and 20 (E,J), and 18 and 28 (F,K). The data of study compounds is contrasted with the data obtained from the treatments with vehicle- and positive control (bromocriptine) or at baseline conditions (no LIRD). The statistical analysis was performed using the Welch′s ANOVA test followed by Dunnett’s T3 post hoc tests. The asterisks signify results from the post hoc tests: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Data is presented as mean ± SEM.