TRR469, a potent A(1) adenosine receptor allosteric modulator, exhibits anti-nociceptive properties in acute and neuropathic pain models in mice.
A(1) adenosine receptors (ARs) have been identified as a potential target for the development of anti-nociceptive compounds. The present study explores the analgesic effects of a novel A(1)AR positive allosteric modulator, TRR469, in different models of acute and chronic pain in mice. To evaluate the allosteric enhancement, in vitro binding experiments were performed. The anti-nociceptive properties were investigated in formalin and writhing tests, and in the streptozotocin-induced diabetic neuropathic pain model. Rotarod and catalepsy tests were used to identify potential side effects, while the functional effect of TRR469 was studied using [(3)H]-d-aspartate release from synaptosomes. TRR469 effectively inhibited nociceptive responses in the formalin and writhing tests, with effects comparable to those of the reference analgesic morphine. Isobolographic analysis of the combination of TRR469 and morphine revealed an additive interaction. TRR469 was anti-allodynic in the neuropathic pain model and did not display locomotor or cataleptic side effects. TRR469 enhanced the binding of the agonist radioligand [(3)H]-CCPA and induced a 33-fold increase of adenosine affinity in spinal cord membranes. In mouse spinal cord synaptosomes, TRR469 enhanced the inhibitory effect of A(1)AR activation on [(3)H]-d-aspartate release, a non-metabolizable analogue of glutamate. In conclusion, this research demonstrates the anti-nociceptive effect of the novel compound TRR469, one of the most potent and effective A(1)AR positive allosteric modulators so far synthesized. The use of TRR469 allows for the possibility of exploiting analgesic properties of endogenous adenosine, with a minor potential to develop the various side effects often associated with the use of direct receptor agonists.
Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Fabrizio
F
Vincenzi
Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Martina
M
Targa
Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Romeo
R
Romagnoli
Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Stefania
S
Merighi
Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Stefania
S
Gessi
Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Pier Giovanni
PG
Baraldi
Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Pier Andrea
PA
Borea
Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address: vrk@unife.it.
Katia
K
Varani
D019342:Acetic Acid / Q000633:toxicity; D000494:Allosteric Regulation; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D002375:Catalepsy / Q000209:etiology / Q000517:prevention & control; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D058905:Purinergic Agents / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
C475229:2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene; C000593530:2-amino-4-((4-(phenyl)piperazin-1-yl)methyl)-5-(4-fluorophenyl)thiophen-3-yl)-(4-chlorophenyl)methanone; D000700:Analgesics; D010879:Piperazines; D058905:Purinergic Agents; D013876:Thiophenes; C075004:PD 81723; D019342:Acetic Acid
A1 adenosine receptors; Acute and chronic pain; Analgesia; Positive allosteric modulator; TRR469