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For centuries Hashish and Marihuana, both derived from the Indian hemp Cannabis Sativa L., have been used for their medicinal, as well as their psychotomimetic effects. The cannabinoids are the C₂₁ compounds typical of and present in cannabis, their carboxylic acids, analogs, and transformation products. A surge of scientific interest followed Gaoni and Mechoulam's report that (-)-trans-delta-9-tetrahydrocannabinol (delta-9-THC) is the major psychopharmacologically active component of cannabis [Y. Gaoni and R. Mechoulam J. Amer. Chem. Soc. 86, 1646-1647, 1964]. Today increasing amounts of information are available on the pharmacological and biochemical effects of delta-9-THC and other cannabinoids. The therapeutic value of these compounds, for example, as analgesics, bronchodilators, anti-convulsants, anti-emetics, and anti-glaucoma agents is also of intense interest.

The long term goal of our cannabinoid research is to elucidate the basis for the actions of the cannabinoids at the molecular level. To date, two cannabinoid receptors have been identified. The first receptor (CB₁) is found largely in the brain [L. Matsuda et al. Nature. 246, 561-564, 1990. C.M. Gerard et al. Biochem. J. 279, 129-134, 1991.] The second cannabinoid receptor (CB₂) is found largely in the periphery. [S. Munro, K.L. Thomas, M. Abu-Shaar Nature, 365, 61-65, 1993.] Both receptors are G-protein-coupled receptors. The focus of most of our work has been on the CB₁ receptor because the SAR of this receptor is better developed.

There are four known structural classes of cannabinoid agonist ligands:

           (1)      the classical cannabinoids (e.g. delta-9-THC)

           (2)      the non-classical cannabinoids (e.g. CP-55,940)

           (3)      the endogenous cannabinoid (e.g. anandamide)

           (4)      the aminoalkylindoles (e.g. WIN-55, 212-2)

Because K3.28A mutation studies of the CB₁ receptor [Z.H. Song and T.I. Bonner Mol Pharmacol. 49,891-896, 1996] have indicated that WIN-55,212-2 may not share the same recognition sites at the CB₁ receptor as do the first three agonist classes, we have developed one pharmacophore for the first three ligand classes (CB₁ Pharmacophore 1) and a separate one for the aminoalkylindoles (CB₁ Pharmacophore 2).

CB₁ Pharmacophore 1

The development of CB₁ pharmacophore 1 was the early focus of our work (see references below). Recent projects concerning the CB₁ Pharmacophore 1 have focused on anandamide. We have found several key requirments for the binding and activation of the CB1 receptor by Class 1-3 ligands. These requirements are:

             (1)      a C-3 side chain of adequate length (5 to 8 carbons long).

             (2)      the presence of a group capable of accepting a hydrogen bond.
                       For Class 1 and 2 ligands the phenolic hydroxyl oxygen is
                       hypothesized to serve as the acceptor. [P.H. Reggio,
                       H.H. Seltzman, D.R. Compton, W.R. Prescott Jr.,and
                       B.R. Marting Mol. Pharmacol. 38,854-862, 1990]. While
                       work on anandamide is currently in progress, it is our
                       hypothesis that the carbonyl oxygen of anandamide serves
                       as the hydrogen bond acceptor.

             (3)      a shape which avoids bulk near the top of the carbocyclic
                       ring in the bottom face of the molecule, termed REV 1
                       [P.H. Reggio, A.M. Panu, and S. Miles J.Med. Chem. 36,
                       1761-1771, 1993.]

             (4)      a shape which avoids the alpha face of the dihydropyran
                       ring of classical cannabinoids, termed REV 2 [M. Perry
                       and P.H. Reggio FASEB Abstract, Spring 1995.]

Using information from our REV 1 (#3 above) and REV 2 (#4 above), we calculated a Receptor Steric Map for classical and non-classical cannabinoids at the CB₁ receptor. This map can be thought of as a representation of the size and shape of the binding cavity for these molecules at the CB₁ receptor. [S.G. Lagu, A.Varona,J.D.Chambers and P.H. Reggio Drup Design and Discovery 12, 179-192, 1995.]

CB₁ Pharmacophore 2 - The Aminoalkylindole Pharmacophore

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