Abstracts

Rationale: The endogenous neuropeptide galanin and its associated receptors are widely expressed in the CNS and are important modulators of neuronal excitability. We previously described the potent anticonvulsant and analgesic activity of NAX 5055, a systemically bioavailable galanin analog (Bulaj et al., J. Med Chem. 2008, White et al.Neurotherapeutics 2009). More recently we reported on a rational approach to engineering systemically bioavailable galanin analogs that can discriminate between GalR-1 and GalR-2 (Robertson et al., J. Med Chem. 2010). The present investigations provide an extended pharmacological characterization of a prototype GalR-2 preferring galanin analog, NAX 1205-1 (1205-1), in rodent models of epilepsy and pain. Methods: The anticonvulsant profile of 1205-1 was evaluated in the mouse 6 Hz (44 mA stimulation), maximal electroshock (MES) and the subcutaneous pentylenetetrazol (scPTZ) seizure tests. In addition, 1205-1 was tested against the fully expressed seizure in hippocampal kindled rats. The analgesic effects of 1205-1 were assessed in the mouse formalin and abdominal constriction tests. 1205-1 was also evaluated for its ability to attenuate mechanical allodynia in the rat partial sciatic nerve ligation (PSL) model. For all studies, mice (CF-1) were tested 1 hour following i.p. administration of 1205-1, the previously determined time to peak effect in mice. Rats (Sprague-Dawley) were tested at multiple time-points following i.p. administration. Results: 1205-1 was potently active in the 44 mA 6 Hz seizure test (ED50 6.6 mg/kg)and was only slightly higher than the previously determined 32 mA stimulation ED50(5.7 mg/kg0. At 1 mg/kg 1205-1 significantly reduced the behavioral seizure score but not the afterdischarge duration in 4 of 8 hippocampal kindled rats tested. 1205-1 was not active against MES and scPTZ evoked seizures at 8 mg/kg. 1205-1 reduced both the acute and inflammatory phases of the mouse formalin pain response (ED50 2.6 and1.7 mg/kg, respectively) and in the abdominal constriction assay (2 mg/kg) it decreased the number of writhes to 15% of control. Lastly, in the PSL model, 1205-1 (1 mg/kg) increased paw withdrawal threshold 2000% of control at 2 hr post-i.p. administration. Conclusions: These results demonstrate that 1205-1 is potently active in rodent models of acute and chronic pain and refractory epilepsy following systemic administration. Like NAX 5055, this GalR-2 preferring analog possesses a unique profile in seizure models by remaining potently active in two models of partial epilepsy; e.g., the 6 Hz 44 mA test and kindled rat. In contrast, it is not active in the MES or scPTZ tests. Ongoing studies continue to evaluate the therapeutic potential of GalR-2 preferring galanin analogs in models of pain and epilepsy to identify a lead candidate with the most favorable efficacy and safety profile. Supported by grants from the Epilepsy Therapy Project, The Epilepsy Foundation of America, and the NINDS, NIH (R21 N5059669). GB and HSW are scientific co-founders of NeuroAdjuvants.