ABSTRACT
Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
Subject(s)
Dopamine Uptake Inhibitors/chemistry , Tetrahydroisoquinolines/chemistry , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/metabolism , Kinetics , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Protein Binding , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/metabolismABSTRACT
A facile synthesis of 1-fluoro-1-deoxy-Delta(8)-THC analogs with side chains seven carbons in length, in the alkane/ene/yne- series (6, 5, and 4), was achieved from 1-fluoro-3,5-dimethoxybenzene (1). In vitro studies show that substitution by a fluorine has a significant detrimental effect on CB1 binding which is supported by in vivo testing. The implications of these results on the SAR of classical cannabinoids are discussed.
Subject(s)
Cannabinoids/chemistry , Cannabinoids/pharmacology , Fluorine/chemistry , Animals , Body Temperature/drug effects , Cannabinoids/chemical synthesis , Indicators and Reagents , Mice , Motor Activity/drug effects , Reaction Time/drug effects , Receptor, Cannabinoid, CB1/drug effects , Structure-Activity RelationshipABSTRACT
The role of the oxygen of the benzopyran substituent of Delta(9)-tetrahydrocannabinol in defining affinity for brain cannabinoid (CB(1)) receptors is not well understood; however, it is known that opening the pyran ring can result in either increased potency and affinity, as in CP 55,940 [(-)-cis-3-[2-hydroxy-4(1,1- dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol], or in an inactive cannabinoid, as in cannabidiol. In the present study, a series of bicyclic resorcinols that resemble cannabidiol were synthesized and tested in vitro and in vivo. Analysis of the structure-activity relationships of these analogs revealed several structural features that were important for maintaining CB(1) receptor recognition and in vivo activity, including the presence of a branched lipophilic side chain and free phenols as well as substitution of a cyclohexane as the second ring of these bicyclic cannabinoids. Many of these analogs exhibited CB(2) selectivity, particularly the dimethoxyresorcinol analogs, and this selectivity was enhanced by longer side chain lengths. Hence, unlike cannabidiol, these resorcinol derivatives had good affinity for CB(1) and/or CB(2) receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB(2)-selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB(1) and CB(2) receptors.
Subject(s)
Anisoles/pharmacology , Cannabinoids/pharmacology , Receptors, Drug/agonists , Resorcinols/pharmacology , Animals , Anisoles/chemistry , Cannabinoids/chemistry , Cyclohexanols , Male , Mice , Mice, Inbred ICR , Receptors, Cannabinoid , Receptors, Drug/metabolism , Resorcinols/chemistry , Structure-Activity RelationshipABSTRACT
In order to make further structural comparisons between tetrahydrocannabinol and anandamide, substituents at C1 and C3 of the phenolic ring of tetrahydrocannnabinol were altered. In order to examine the alignment of the phenolic hydroxyl of tetrahydrocannnabinol with the hydroxyl group of anandamide, 1-fluoro-1-deoxy-tetrahydrocannnabinol analogs were prepared. These analogs had low affinity for the CB(1) cannabinoid receptor and were considerably less potent than tetrahydrocannnabinol in producing pharmacological effects in mice. These results suggest that these two oxygen moieties do not overlap. Additionally, the fact that a fluorine group can only accept hydrogen bonds suggest that the phenolic oxygen at the C1 position of tetrahydrocannnabinol donates electrons for hydrogen bonding rather than the hydrogen of the hydroxyl group interacting with the receptor. Additionally, substitution of a fluorine for the hydroxyl group at C1 led to analogs with higher affinity for CB(2) than CB(1) cannabinoid receptors, thereby underscoring a fundamental difference in the binding properties of these two receptor subtypes.
