All oxime analogs showed comparable affinity at the CB2 receptor, but surprisingly they were found to function as inverse agonists for CB2.In behavioral studies (i.e. analgesia, hypothermia) trans-oxime 8a exhibited a predictable fast onset (∼20 min) and short duration of pharmacological action (∼180 min), in contrast to the very prolonged duration of Δ<sup>8</sup>-THC-DMH (>24 h), thus limiting the potential for severe psychotropic side-effects associated with persistent activation of the CB1 receptor.
Herein, we describe a versatile total synthesis of (-)-<i>cis</i>-PET and its (-)-<i>trans</i> diastereoisomer and demonstrate that both molecules readily penetrate the brain and induce hypothermia, catalepsy, hypolocomotion, and analgesia in a CB1 receptor-dependent manner in mice.
In addition, in BALB/c male mice, acute oral administration of WOBE437 (50 mg/kg) exhibited similar brain concentrations after 60 min and inhibited analgesia in the hot plate test in a cannabinoid CB1 receptor-dependent manner, without inducing catalepsy or affecting locomotion.
Both hypothermia and analgesia were blocked by the CB1 receptor inverse agonist rimonabant, but the pronounced hypolocomotion was CB1 receptor-independent.