Chromenopyrazoles: non-psychoactive and selective CB₁ cannabinoid agonists with peripheral antinociceptive properties.
The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB₁-mediated side effects are due to the fact that CB₁ receptors are largely expressed in the central nervous system (CNS). As it is known that CB₁ receptors are also located peripherally, there is growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed analogously to the classical cannabinoid cannabinol were synthesized, characterized, and tested for cannabinoid activity. Radioligand binding assays were used to determine their affinities at CB₁ and CB₂ receptors. Structural features required for CB₁/CB₂ affinity and selectivity were explored by molecular modeling. Some compounds in the chromenopyrazole series were observed to be selective CB₁ ligands. These modeling studies suggest that full CB₁ selectivity over CB₂ can be explained by the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. In vivo behavioral tests were then carried out on the most effective CB₁ cannabinoid agonist, 13 a. Chromenopyrazole 13 a did not induce modifications in any of the tested parameters on the mouse cannabinoid tetrad, thus discounting CNS-mediated effects. This lack of agonistic activity in the CNS suggests that this compound does not readily cross the blood-brain barrier. Moreover, 13 a can induce antinociception in a rat peripheral model of orofacial pain. Taking into account the negative results obtained with the hot-plate test, the antinociception induced by 13 a in the orofacial test could be mediated through peripheral mechanisms.
Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
Jose
J
Cumella
Laura
L
Hernández-Folgado
Rocio
R
Girón
Eva
E
Sánchez
Paula
P
Morales
Dow P
DP
Hurst
Maria
M
Gómez-Cañas
Maria
M
Gómez-Ruiz
Diana C G A
DC
Pinto
Pilar
P
Goya
Patricia H
PH
Reggio
María Isabel
MI
Martin
Javier
J
Fernández-Ruiz
Artur M S
AM
Silva
Nadine
N
Jagerovic
D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism; D018373:Peripheral Nervous System Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism
D000700:Analgesics; D001578:Benzopyrans; D002186:Cannabinoids; D018373:Peripheral Nervous System Agents; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2