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The fourth chemical class of cannabinergic ligands, the aminoalkylindoles (AAIs) were initially developed at Sterling Winthrop as potential non-ulcerogenic analogs of non-steroidal anti-inflammatory drugs (NSAIDs) (Bell et al. 1991) and bear no structural relationship to the cannabinoids. These analogs also exhibited antinociceptive properties that eventually were attributed to their interactions with the cannabinoid receptors (D'Ambra et al. 1992; Eissenstat et al. 1995). The most widely studied compound of this series is WIN-55,212-2 (33, Fig. 9), a potent CBi and CB2 agonist with a slight preference for CB2. Cannabinergic activity resides principally with only one optical antipode and is more potent than 49-THC in several pharmacological and behavioral assays (Compton et al. 1992; Martin et al. 1991). WIN-55,212-2 has played an important role in the identification and characterization of cannabinoid receptors and their associated functions and is now in standard use as a CB^CB2 radioligand. The four pharmacophores identified for the aminoalkylindoles are: (1) C-3 substituents, (2) the N-1 aminoalkyl side chain, (3) C-2 substituents, and (4) indole ring substituents and modifications. The SAR requirements of this class of compounds are summarized as follows:

SAR of Aminoalkylindoles

C-3 Substituents Pravadoline (34,Fig. 9), whichcarriesap-methoxybenzoyl group at C-3, was used as a benchmark ligand to explore structural requirements at this site (Eissenstat et al. 1995). Its o-methoxy isomer exhibits higher potency. However, ort^o-substitution with other groups such as -CH3, -OH, -Cl, -CN, or -F diminishes activity. The presence of an ethyl group at the para position improves potency, but further increase in chain length results in diminished potency. The 1-naphthoyl substitution at C-3 is more potent (IC50 = 19 nM) than the 2-napthoyl analog (IC50 = 128 nM). Replacement of the naphthyl ring with an alkyl (e.g., CH3) or alkenyl [(CH3)2C=CH] groups results in complete loss of CB1 receptor affinity (K> 10,000 nM) (Huffmann et al. 1994).

NMR and X-ray crystallography studies of 34 and its C-2H congener have revealed that AAIs can exist in two distinct conformations based on the orientation of the C-3 aroyl system (Bell et al. 1991; Reggio et al. 1998). In the s-trans conformation, which predominates when the C-2 substitution is hydrogen, the aryl group is proximal to C-2, while the carbonyl oxygen atom is located near C-4. In the s-cis conformation, which predominates when the C-2 substituent is a methyl group, the conformational preference shows the aryl ring to be located near C-4, and the carbonyl oxygen near C-2.

Naphthylidene-substituted aminoalkylindenes (e.g., 35, Fig. 9), a conformation-ally more rigid version of initial AAIs, were originally designed to circumvent the CNS side effects of pravadoline (Kumar et al. 1995). These analogs were tested as a mixture of E- and Z-isomers and exhibited higher CB1 affinity compared to pravadoline. Later, it was shown that the CB1 and CB2 affinities and pharmacological potencies were higher for the E-geometric isomer (35, s-trans, Fig. 9) compared to the Z-isomer (Reggio et al. 1998). Removal of the carbonyl oxygen of the C-3 aroyl group in AAIs having unsubstituted C-2 results in moderate reduction in affinity for CB1 compared to their carbonyl precursors (Huffman et al. 2003a). However, the loss of affinity is larger in the 2-methyl substituted analogs (e.g., 36, Fig. 9). Both observations support the hypothesis that the s-trans conformation of AAI analogs such as 33 is the preferred conformation for interaction at both CB1

Fig. 9. C-3 modified cannabinergic aminoalkylindoles

and CB2 receptors and that aromatic stacking of the ligands with aromatic residues in helices 3,4, and 5 of both receptors may be an important interaction for AAIs at these receptors (Burley and Petsko 1985; Huffman et al. 2003a; Reggio et al. 1998).

The spatial and electronic requirements of the C-3 substituent were further explored by introducing a C-3 amide group (Bristol Myers Squibb). The AAI C-3 amide ligand 37 (Fig. 9) with a methoxy group at C-7, exhibited high CB2 affinity (K = 8 nM) and selectivity (CB1/CB2 = 500) (Hynes et al. 2002). Replacement of the amino acid moiety in 37 with the S-fenchylamine component resulted in slightly reduced affinity for the CB2 receptor (K = 30 nM). However, in the S-fenchyl amide series, when the 2-methyl group in indole was replaced by hydrogen, the resulting ligand (38, Fig. 9) showed improved CB2 affinity (Kj = 11 nM).

The 4-alkyloxy indole analogs were derived by translocating the C-3 substituent of AAIs to C-4 via an ether linkage. Some of these exhibited in vivo cannabimimetic activity, but most of them lacked cannabinoid receptor affinity (Dutta et al. 1997).

Alkyloxy Indole
Fig. 10. Chemical structures of some aminoalkylindole-derived analogs

N-1 Aminoalkyl Chain A number of indole analogs bearing different aminoalkyl substituents at N-1 were synthesized (N-attached analogs, e.g., 34,Fig. 9)andtested (Eissenstat et al. 1995). This study found the aminoethyl substitution as an optimal requirement with morpholino, thiomorpholino, and piperidino analogs showing the highest activities. The respective acyclic amine and piperazine analogs were inactive.

The Sterling Winthrop and Makriyannis laboratories further explored structural requirements at the N-1 position by synthesizing novel analogs in which the aminoalkyl chain of the indole ring is attached to a heterocyclic amine through a C-C bond. These analogs are generally more potent compared to the C-N analogs and exhibit more favorable physicochemical properties. Potency was optimum for N-methylpiperidinyl-2-methyl substitution at the N-1 position (39, Fig. 10), while activity resided predominately in the R-enantiomer (D'Ambra et al. 1996).

AM1241 (40, Fig. 10), a highly CB2-selective and potent agonist (Ibrahim et al. 2003; Malan et al. 2001) was recently developed by Makriyannis. Design of this molecule incorporated the N-methylpiperidinyl-2-methyl substituent at the N-1 position and a novel 2-iodo-5-nitrobenzoyl group at C-3. AM1241 exhibits remarkably high peripheral analgesia in vivo and does not produce catalepsy, hypothermia, inhibition of spontaneous locomotor activity, or impairment of performance on the rotarod apparatus. The potential use of this CB2 receptor agonist for the treatment of neuropathic pain is being explored.

Replacement of the aminoalkyl substituent by an alkyl chain results in N-alkyl indoles (non-AAIs) (e.g., 41, Fig. 10). The SAR of cannabimimetic 2-methylindoles indicates that compounds with N-alkyl substituents from w-propyl to w-hexyl have good affinities for both CB1 and CB2 receptors with a preference for CB2. The in vivo potencies of these compounds were reported to be consistent with their receptor affinities (Huffmann et al. 1994; Wiley et al. 1998).

C-2 Substituents Analysis of the effect of C-2 substitution on cannabinoid receptor affinity in AAIs reveals a strong preference for a small substituent at C-2. Thus, hydrogen or methyl groups are well tolerated with the C-2H analogs exhibiting slightly higher affinities for the CB2 than C-2 methyl analogs (Eissenstat et al. 1995; Hynes et al. 2002; Wrobleski et al. 2003).

Recently, researchers at Bristol Myers Squibb reported their discovery of inda-zole carboxamides (e.g., 42, Fig. 10), a new class of cannabimimetics, in which the C-2 carbon of 3-amido AAIs (e.g., 38, Fig. 9) is replaced by nitrogen. The indazole analog 42 exhibits high affinity for the CB2 receptor (K = 2.0 nM) compared to the corresponding AAI analogs 38 (Wrobleski et al. 2003). Indolopyridones (e.g., 43, Fig. 10), which are conformationally restricted C-3 amido AAIs, exhibit increased affinities for the CB2 receptor (K = 1.0 nM) and possess anti-inflammatory properties when administered orally in an in vivo murine inflammation model (Wrobleski et al. 2003).

Indole Ring Substituents and Modifications Introduction of a methyl group at C-4 or various substituents such as -CH3, -OCH3, -F, -Br, or -OH groups at C-5 of pravadoline diminishes affinity. Conversely, C-6 substitution with -CH3, -OCH3, or -Br (WIN-54,461,bromopravadoline) groups improves receptor affinity, but the ligands exhibit diminished agonist properties (Eissenstat et al. 1995). Incorporation of an iodo group at C-6 led to AM630 (44, Fig. 10), a ligand that exhibits improved affinity as well as selectivity for CB2 (Hosohata et al. 1997a,b; Pertwee et al. 1995). This compound was shown to be a potent and selective antagonist/inverse agonist for CB2 and is a useful pharmacological tool developed before its principal target site was identified (Ross et al. 1999). Substitution at C-7 gives modest improvement in binding affinity. Potent AAI analogs were generated by conformationally restricting the N-1 side chain through the formation of a six-membered ring between the N-1 and C-7 substituents (D'Ambra et al. 1992). In N-alkyl indoles, replacement of the indole phenyl ring with a cyclohexyl ring led to an analog with reduced affinities for both CBi and CB2 (Tarzia et al. 2003). Removal of the phenyl ring in AAIs or non-AAIs led to a pyrrole class of cannabimimetics (e.g., 45, Fig. 10). The SAR of pyrrole cannabinoids has been explored first by Sterling Winthrop and later by Huffman (Wiley et al. 1998) and Tarzia et al. (2003). Most of the pyrrole-derived analogs are less potent than the corresponding indole derivatives. However, the 4-bromopyrrole analog (Tarzia et al. 2003) exhibits high affinity for both CB1 and CB2 (EC50 = 13.3 nM for rCB: and 6.8 nM for hCB2) comparable to WIN-55,212-2.

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