Cannabinoid Receptors and Their Ligands: Ligand–Ligand and Ligand–Receptor Modeling Approaches 273antagonistic activities and in general exhibited high CB 1 vs CB 2 receptor subtype
selectivities (Lange et al. 2004). The binding affinities of these new compounds
were rationalized using the binding site model proposed by Hurst and co-workers
(2002)
7
Conclusions
This chapter clearly shows that there has been great growth in our knowledge of
the CB receptors and their ligands in the past decade. Pharmacophores have been
developed for the CB 1 antagonist SR141716A and for every structural class of CB 1
agonist. Attempts at creating a unified pharmacophore for all CB 1 ligands have not
met with success. This is likely because CB 1 ligands do not share a single binding
site. CB 2 -selective ligand development has been one of the major advances in the
CB field in the past decade, and information about GPCR structure combined with
mutation studies has permitted refinement of CB 1 and CB 2 receptor models.
Many future challenges for SAR and pharmacophore development still exist. No
pharmacophores have yet been developed for agonist or antagonist recognition
at CB 2. Another major frontier in modeling studies of CB receptors will be the
elucidation of how the CB receptors are activated by agonists and how they are
inactivated by inverse agonists. Methodologically, this will be a challenge because
the timescale over which activation takes place [milliseconds for receptors with
diffusible ligands (Ghanouni et al. 2001b)] is orders of magnitude longer than the
timescales currently accessible computationally ( nanoseconds). In addition, there
is growing evidence that there may be more than one activated state for a GPCR,
with the activated conformational state dependent on the agonist that induced it
(Ghanouni et al. 2001a). This is very likely the situation in the CB field as well
(Glass and Northup 1999) and could present us with the opportunity ultimately
to develop highly selective CB ligands that couple through a specific G protein
subtype.
Acknowledgements.
This work was supported by the National Institute on Drug Abuse (Grants DA03934 and
DA000489).
References
Abadji V, Lin S, Taha G, Griffin G, Stevenson LA, Pertwee RG, Makriyannis A (1994) (R)-
Methanandamide: a chiral novel anandamide possessing higher potency and metabolic
stability. J Med Chem 37:1889–1893
Abood ME, Ditto KE, Noel MA, Showalter VM, Tao Q (1997) Isolation and expression of
a mouse CB1 cannabinoid receptor gene. Comparison of binding properties with those
of native CB1 receptors in mouse brain and N18TG2 neuroblastoma cells. Biochem
Pharmacol 53:207–214