Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1.

Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.

[INCREMENT]9-Tetrahydrocannabinol discriminative stimulus effects of AM2201 and related aminoalkylindole analogs in rats.

The recent recreational use of synthetic cannabinoid ligands, collectively referred to as 'Spice', has raised concerns about their safety and possible differences in their biological effect(s) from marijuana/Δ-tetrahydrocannabinol (THC). AM2201, a highly efficacious, potent cannabinoid receptor 1 (CB1R) agonist, is a recently detected compound in 'Spice' preparations. Furthermore, structural analogs of AM2201 are now being found in 'Spice'. The present studies were conducted to investigate their Δ-THC-like effects using drug (Δ-THC) discrimination in rats. Results show that the tested compounds were potent cannabinergics that generalized to the response to Δ-THC, with AM2201 being most potent, exhibiting a 14-fold potency difference over Δ-THC. The other analogs were between 2.5-fold and 4-fold more potent than THC. Surmountable antagonism of AM2201 with the selective CB1R antagonist/inverse agonist rimonabant also established that the discrimination is CB1R dependent. Time-course data reveal that AM2201 likely peaks rapidly with an in-vivo functional half-life of only 60 min. The present data confirm and extend previous observations regarding Δ-THC-like effects of 'Spice' components.

Probing the carboxyester side chain in controlled deactivation (-)-δ(8)-tetrahydrocannabinols.

We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (-)-Δ(8)-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain's polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action.

"Herbal incense": designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays.

Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called "Spice". The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar "subjective high" with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new "designer" cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics.

Controlled-deactivation cannabinergic ligands.

We report an approach for obtaining novel cannabinoid analogues with controllable deactivation and improved druggability. Our design involves the incorporation of a metabolically labile ester group at the 2'-position on a series of (-)-Δ(8)-THC analogues. We have sought to introduce benzylic substituents α to the ester group which affect the half-lives of deactivation through enzymatic activity while enhancing the affinities and efficacies of individual ligands for the CB1 and CB2 receptors. The 1'-(S)-methyl, 1'-gem-dimethyl, and 1'-cyclobutyl analogues exhibit remarkably high affinities for both CB receptors. The novel ligands are susceptible to enzymatic hydrolysis by plasma esterases in a controllable manner, while their metabolites are inactive at the CB receptors. In further in vitro and in vivo experiments key analogues were shown to be potent CB1 receptor agonists and to exhibit CB1-mediated hypothermic and analgesic effects.

Antagonism of ∆9-THC induced behavioral effects by rimonabant: time course studies in rats.

The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ∆9-tetrahydrocannabinol (∆9-THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ∆9-THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ∆9-THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose-response functions of ∆9-THC and the time course for rimonabant in its ability to block the discriminative stimulus effects of ∆9-THC. For antagonism testing, the training doses of ∆9-THC were used and the rimonabant dose was 1mg/kg. Tests were 20, 60, 120, and 240 min post rimonabant administration; ∆9-THC was always administered 20 min prior to testing. For EXP-2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ∆9-THC, rimonabant and combinations of the drugs. The ED(50) estimates for the dose-response functions were 0.38 (±0.28-0.51) and 0.50 (±0.40-0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ∆9-THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (±95.7-172.2) and 98.4 (±64.2-150.7) min by rimonabant for the two groups in EXP-1, respectively. Similarly, the functional half-life of rimonabant was 118.9 (±66.1-213.9) min in EXP-2. Thus, antagonism of ∆9-THC by rimonabant is relatively short lasting.