RESUMEN
In this study, we determined mode of action of a novel carbamoyloxy arylalkanoyl arylpiperazine compound (SKL-NP) on hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents (I(h)) that plays important roles in neuropathic pain. In small or medium-sized dorsal root ganglion (DRG) neurons (<40 µm in diameter) exhibiting tonic firing and prominent I(h), SKL-NP inhibited I(h) and spike firings in a concentration dependent manner (IC(50)=7.85 µM). SKL-NP-induced inhibition of I(h) was blocked by pretreatment of pertussis toxin (PTX) and N-ethylmaleimide (NEM) as well as 8-Br-cAMP, a membrane permeable cAMP analogue. These results suggest that SKL-NP modulates I(h) in indirect manner by the activation of a Gi-protein coupled receptor that decreases intracellular cAMP concentration. Taken together, SKL-NP has the inhibitory effect on HCN channel currents (I(h)) in DRG neurons of rats.
RESUMEN
A series of carbamic acid 1-phenyl-3-(4-phenyl-piperazine-1-yl)-propyl ester derivatives were synthesized through discovery strategies for balancing target-based in vitro screening and phenotypic in vivo screening. All the newly synthesized compounds were screened for their analgesic activities and compared with standard drug morphine. Among them, compound 44r, a potent analgesic agent that has favorable pharmacokinetic properties in rats and most importantly, has a wide safety margin. We demonstrated with in vitro and in vivo functional assays that its analgesic activity might be through 5-HT(2A) antagonism to some extent. Hence, it is concluded that there is ample scope for further study in developing compound 44r as a good lead candidate for an analgesic agent.
Asunto(s)
Analgésicos/síntesis química , Carbamatos/síntesis química , Dolor/tratamiento farmacológico , Piperazinas/síntesis química , Antagonistas de la Serotonina/síntesis química , Analgésicos/farmacología , Animales , Carbamatos/farmacología , Ésteres , Ratones , Estructura Molecular , Morfina/farmacología , Dimensión del Dolor , Piperazinas/farmacología , Ratas , Receptores de Serotonina 5-HT2/metabolismo , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
The vast majority of human peripheral nerve injuries occur in the upper limb, whereas the most animal studies have been conducted using the hindlimb models of neuropathic pain, involving damages of the sciatic or lumbar spinal nerve(s). We attempted to develop a rat forelimb model of peripheral neuropathy by partial injury of the median and ulnar nerves. The halves of each nerve were transected by microscissors at about 5mm proximal from the elbow joint and behavioral signs of neuropathic pain, such as mechanical and cold allodynia, and heat hyperalgesia, were monitored up to 126 days following nerve injury. Mechanical allodynia was assessed by measuring the forepaw withdrawal threshold to von Frey filaments, and cold allodynia was evaluated by measuring the time spent in lifting or licking the forepaw after applying acetone to it. Heat hyperalgesia was also monitored by investigating the forepaw withdrawal latencies using the Hargreaves' test. After the nerve injury, the experimental animals exhibited long-lasting clear neuropathic pain-like behaviors, such as reduced forepaw withdrawal threshold to von Frey filaments, the increased response duration of the forepaw to acetone application, and the decreased withdrawal latency to radiant heat stimulation. These behaviors were significantly alleviated by administration of gabapentin (5 or 50mg/kg, i.p.) in a dose-dependent manner. Therefore, these abnormal sensitivities are interpreted as the signs of neuropathic pain following injury of the median and ulnar nerves. Our rat forelimb model of neuropathic pain may be useful for studying human neuropathic pain and screening for valuable drug candidates.