Development of ligands at γ-aminobutyrric acid type A (GABAA) receptor subtype as new agents for pain relief

Abstract

The identification of compounds with selective anxiolytic-like effects, exerted through the benzodiazepine site on γ-aminobutyric acid type A (GABA(A)) receptors, and that show pronounced antihyperalgesia in several pain models, has oriented research towards the development of new agents for the relief of pain. Starting from our previously reported ligands at the benzodiazepine site on GABA(A) receptors showing selective anxiolytic-like effects, we have designed new compounds with the aim of identifying those devoid of the typical side effects of the classical benzodiazepines. Our preliminary results indicate that compounds 4, 10(±) and 11 have a very promising antihyperalgesic profile in different animal pain models (peripheral mono-neuropathy, STZ-induced hyperalgesia). In particular 11 exhibits high potency since it exerted its protective effect starting from the dose of 3mg/kg po, after single injection.

Synthesis and Pharmacological Evaluation of Novel GABAA Subtype Receptor Ligands with Potential Anxiolytic‐like and Anti‐hyperalgesic Effect

“…Derivative 12 is the 7‐isomer of our lead compound A , (3‐iodo‐8‐benzylaminopyrazolo[5,1‐c][1,2,4]benzotriazine 5‐oxide Fig. ), characterized by a selective anxiolytic profile joined to anti‐hyperalgesic effects in animal pain models, starting from the dose of 3 mg kg −1 per os . Accordingly to the notion that the benzodiazepines are generally not analgesic per se , the GABA A ‐subtype ligands can exert anti‐hyperalgesic action overall when the pain sensitivity is pathologically increased (inflammation or neuropathic injury) .…”

“…On the basis of binding results, it emerges that only derivatives bearing the 7‐benzylamino group ( 11a , 12 , and 13a ) show receptor recognition ( K i range 0.28–5.08 μM). Thus it is possible to hypothesize that, despite the simultaneous presence of a lipophilic group at position 3 (I and CH 3 ) and of a group that engages a hydrogen bond at 7‐position (NH), a different fit into receptor protein with respect the 8‐isomers occurs (data not published). The same trend is verified also in the 3‐triazole derivatives ( 18a and 21a ).…”

“…Our research group has been extensively involved in the design and synthesis of pyrazolo[5,1‐c][1,2,4]benzotriazine (PBT) derivatives, with the aim to identify selective GABA A ‐R subtype (Bdz site) ligands. Our previous studies let us to individuate the 3‐iodo‐8‐benzylamino PBT (lead A ) reported in Figure , a promising compound with K i = 0.109 ± 0.008 nM and provided with selective anxiolytic and anti‐hyperalgesic effect, thus acting as a α2‐subtype agonist. Its pain relieving efficacy was preclinically shown against trauma‐induced peripheral nerve pain neuropathy and diabetic neuropathy, taking effect at 3 mg kg −1 per os.…”

“…Because the importance of the 8‐NH group for the anxiolytic and anti‐hyperalgesic effect was highlighted in the series of 3,8‐disubstituted PBT , we aimed to verify if the shift of the NH from 8‐ to 7‐position still allows the pharmacological activity. Thus, we synthesized 7‐arylalkylaminopyrazolo [5,1‐c][1,2,4benzotriazines 3‐substituted (I, CH 3 , triazole) to optimize lead A . Moreover, some 8‐arylalkylaminoderivatives were synthesized ad hoc to better compare the two series.…”

GABAA receptor modulation: Potential to deliver novel pain medicines?

“…Recently, a number of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives developed as anxiolytics without sedative or myorelaxant properties have also been reported to possess anti-hyperalgesic properties in chronic constriction injured rats and in rats with streptozocin-induced neuropathic pain (Guerrini et al, 2011). Of the optimized compounds tested (e.g., compound 11; 3-iodo-8-benzylaminopyrazolo [5,1-c][1,2,4]benzotriazine5-oxide) binding affinity reached sub-nanomolar values and provided reasonably potent antihyperalgesic efficacy (3 mg/kg) after oral administration.…”