Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects

Abstract

Aim Cannabinoid receptor type 1 (CB1) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. Methods This was a double‐blind, randomized, placebo‐controlled, crossover study. On occasions 1–4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK−PD modelling. Results The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half‐life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [−26.70% [90% confidence interval (CI) −40.9, −12.6%]; −7.10%, (90%CI −18.1, 5.3%); −7.30%, (90% CI −11.5%, −3.0%) respectively] and TM38837 500 mg [−22.10% (90% CI −34.9, −9.4%); −12.20% (90% CI −21.6%, −1.7%); −8.90% (90% CI −12.8%, −5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents

“…These compounds exhibited CB1 receptor antagonistic activity equal to or less than 10 µM. (147)(148)(149) Maitra et al [126] invented novel peripherally restricted diphenyl purine derivatives that did not cross the BBB and thus minimized CNS-related side effects. Compound (150) exhibited a K i value of 0.355 µM with CB1/CB2 ratio of 30.2.…”

“…Further development of compounds of this class may be beneficial for the pharmacotherapy of this metabolic disorder. Another company 7TM Pharma [147] has also identified compound TM38837 [148], a second-generation CB1 receptor antagonist that acts peripherally [149] and has the potential to treat several metabolic disorders without CNS side effects. In 2010, the company announced that they have successfully conducted and completed Phase I clinical trials of compound TM38837 for the treatment of obesity and related metabolic disorders [147] and this type of compound should be further developed.…”

Components of the cannabinoid system in the dorsal periaqueductal gray are related to resting heart rate

“…Typically, systemic administration of cannabinoids evokes a depressor and bradycardic response (32, 35, 58), attributed, in part, to activation of peripheral CB 1 Rs on autonomic nerves innervating the heart and on sympathetic nerves innervating the vascular smooth muscle. Yet, in humans, the prominent and most consistent response to the cannabinoid Δ 9 -tetrahydrocannabinol (THC) is a CB 1 R-dependent increase in heart rate (25, 30). This tachycardia, which is usually accompanied by a small increase in blood pressure and an increase in cardiac output, is attributed to an increase in cardiac sympathetic nerve activity and a decrease in cardiac parasympathetic nerve activity (2).…”

“…This tachycardia, which is usually accompanied by a small increase in blood pressure and an increase in cardiac output, is attributed to an increase in cardiac sympathetic nerve activity and a decrease in cardiac parasympathetic nerve activity (2). While there is evidence for the involvement of peripheral CB 1 Rs in the increase in heart rate (30, 55), many studies support a centrally mediated contribution (3, 27, 43). Recent studies suggest that central administration of cannabinoids primarily evokes a sympathoexcitatory and vagal inhibitory response mediated by CB 1 Rs.…”

Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity

“…7TM Pharma discovered diaryl pyrazole TM38837 (b), a peripherally acting CB1 receptor antagonists which showed a brain-to-plasma ratio of 1:33 [16]. The data suggested that a 100-mg dose of TM38837 did not show any central nervous system (CNS) side effects as it did not enter into the brain [17]. Similarly, AM6545 (c), a diaryl pyrazole derivative, offered very promising results as peripheral CB1 receptor antagonist [18].…”