Structural Requirements for Cannabinoid Receptor Probes 225Fig. 12.3,4-Disubstituted pyrazolines
C-5 SubstituentsThe 4-chloro group of the phenyl ring can be replaced by bromo
or alkyl groups but not by nitro or amino groups (Lan et al. 1999; Thomas et
al. 1998; Wiley et al. 2001). Replacement of 4-chloro with a 4-iodo substituent
(AM251) leads to optimal CB 1 affinity and CB 1 /CB 2 selectivity. AM251 has proved
to be an excellent CB 1 probe and is widely used as a standard. Conversely, re-
placement of the aromatic ring with alkyl groups abolishes CB 1 affinity(Lanetal.
1999).
Recently, two research groups independently reported a number of rigid analogs
of SR141716A. Solvay (Stoit et al. 2002) first reported some tricyclic CB 1 -selective
ligands in which the 4- and 5-substituents are conformationally restricted through
theformationofarelativelyrigidtricyclicsystem.Inthesecompoundsthe4-methyl
group is connected with theorthoposition of the aromatic 5-aryl substituent to
form benzocycloheptapyrazole analogs represented by 50 (Fig. 11) that exhibited
higher CB 1 affinity than the parent SR141716A (Stoit et al. 2002). However, the
compound had poor oral bioavailability. Later Pinna and co-workers (Mussinu et
al. 2003) reported similar tricyclic pyrazole analogs in which the above additional
7-membered ring was replaced by a five-membered ring. Interestingly, most lig-
ands in this class had high affinity and selectivity for CB 2 compared to 50 and
SR141716A.
Very recently, Solvay Pharmaceuticals (Lange et al. 2004) reported a novel class
of 3,4-disubstituted pyrazoline analogs exhibiting high CB 1 selectivity (e.g., 51 ,
Fig. 12). Another novel class of CB 1 antagonists that has received only limited
attention includes the 3-alkyl-5-arylhydantoins (Ooms et al. 2002).
While the search for high affinity/efficacy ligands is ongoing, the development
of well-designed radiolabeled ligands has enhanced our understanding of the
physiological role of the endocannabinoid system. [^123 I]AM281, an^123 I-labeled
1,5-biarylpyrazole, has served as a useful imaging agent in single photon emission
computed tomography (SPECT) studies (Gatley et al. 1997, 1998; Gifford et al.
1997).