C1‘-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols

• Published in: Journal of medicinal chemistry Vol. 50; no. 17; pp. 4048 - 4060
• Main Authors: Papahatjis, Demetris P, Nahmias, Victoria R, Nikas, Spyros P, Andreou, Thanos, Alapafuja, Shakiru O, Tsotinis, Andrew, Guo, Jianxin, Fan, Pusheng, Makriyannis, Alexandros
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.08.2007; Amer Chemical Soc
• Subjects: Animals; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Binding Sites; Biological and medical sciences; Chemistry, Medicinal; Cyclobutanes - chemical synthesis; Cyclobutanes - chemistry; Cyclobutanes - pharmacology; Dronabinol - analogs & derivatives; Dronabinol - chemical synthesis; Dronabinol - pharmacology; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prosencephalon - metabolism; Radioligand Assay; Rats; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Synaptosomes - metabolism; CB2 RECEPTORS; REQUIREMENTS; ANALOGS; CONFORMATIONAL PROPERTIES; CLASSICAL CANNABINOIDS; DELTA-TETRAHYDROCANNABINOL; RAT-BRAIN; CANNABINOID RECEPTOR-LIGAND; IDENTIFICATION; PHARMACOLOGICAL EVALUATION; CB1 cannabinoid receptor; Rat; Ligand; Selectivity; Cannabinoid; Cycloalkane; Oxygen heterocycle; Modeling; Structure activity relation; Molecular model; Aromatic compound; Drug of abuse; Chemical synthesis; Monocyclic compound; Ring size; Terpenoid; Rodentia; CB2 cannabinoid receptor; Tricyclic compound; In vitro; Vertebrata; Biological fixation; Mammalia; Side chain; Mouse; Animal; Phenols; Affinity
• DOI: 10.1021/jm070121a
• ISSN: 0022-2623

In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1‘-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1‘-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1‘-cyclopropyl and C1‘-cyclopentyl groups are optimal pharmacophores for both receptors while the C1‘-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1‘-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2‘−C3‘ cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs.