Analgesic-like activity of piperazine derivatives of 3,3-disubstituted pyrrolidine-2,5-diones in mice

Serotonin (5-HT) and its receptors play a multifaceted role in pain modulation. Among the many subtypes of 5-HT receptors potentially contributing to medullo-spinal modulation of pain, 5-HT1A and 5-HT7 receptors have significant role, as it is expressed both in supraspinal and spinal areas. A series of newly synthesized 3,3-disubstituted pyrrolidine-2,5-diones with affinity for 5-HT1A and 5-HT7 receptors was investigated in some behavioral tests in mice. Previous studies showed antiepileptic activity of these compounds in experimental models of seizures, i.e. induced by pentylentetrazole, maximal electroshock, and psychomotor ones (6-Hz). Many antiepileptic drugs (e.g. carbamazepine, valproinic acid) possess analgesic activity, especially in neuropathic pain treatment. Hence it was an intriguing question, if these new structures may be useful as an analgesics. An antinociceptive effect of four new 3,3-disubstituted pyrrolidine-2,5-diones (JOP364, JOP362, JOP346, and JOP315) was determined in model of acute pain: the hot-plate (phasic pain model) and their activity was compared with effects of the reference drugs tramadol and morphine. Measured antinocicepitve latency of two investigated compounds (JOP364 and JOP 362) in the hot plate test was comparable with tramadol, while the compound JOP315 was inactive in this test. The obtained results entitle to lead further examinations to establish mechanism(s) of analgesic activity of these new derivatives and to estimate their potential therapeutic value.