Pharmacological characterization of novel water-soluble cannabinoids.
Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes. One strategy for solubilizing water-insoluble tetrahydrocannabinols is conversion of the phenolic hydroxyl to a morpholinobutyryloxy substituent. The hydrochloride salts of these analogs are water-soluble and active in vivo when administered in saline. The present investigation demonstrated that hydrochloride salts of numerous substituted butyryloxy esters are water-soluble and highly potent. The substitutions include piperidine, piperazine, and alkyl-substituted amino moieties. It was also discovered that incorporation of a nitrogenous moiety in the alkyl side chain increased the pharmacological potency of tetrahydrocannabinol. For example, an analog containing a pyrazole in the side chain (O-2545) was found to have high affinity and efficacy at cannabinoid 1 (CB(1)) and CB(2) receptors, and when dissolved in saline, it was highly efficacious when administered either intravenously or intracerebroventricularly to mice. A series of carboxamido and carboxylic acid amide analogs exhibited high pharmacological potency, but their hydrochloride salts were not water-soluble. On the other hand, incorporation of imidazoles into the terminus of the side chain led to water-soluble hydrochloride salts that were highly potent when administered in saline to laboratory animals. It is now possible to conduct cannabinoid research with agonists that are water-soluble and thus obviating the need of solubilizing agents.
Martin
Billy R
BR
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. martinb@hsc.vcu.edu
Wiley
Jenny L
JL
Beletskaya
Irina
I
Sim-Selley
Laura J
LJ
Smith
Forrest L
FL
Dewey
William L
WL
Cottney
Jean
J
Adams
Julia
J
Baker
James
J
Hill
David
D
Saha
Bijali
B
Zerkowski
John
J
Mahadevan
Anu
A
Razdan
Raj K
RK
D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002186:Cannabinoids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D002186:Cannabinoids; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; C000603032:O-2545; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)