CHEMISTRY AND BIOLOGY OF THE 2-BETA-ALKYL-3-BETA-PHENYL ANALOGS OF COCAINE - SUBNANOMOLAR AFFINITY LIGANDS THAT SUGGEST A NEW PHARMACOPHOREMODEL AT THE C-2 POSITION
Ap. Kozikowski et al., CHEMISTRY AND BIOLOGY OF THE 2-BETA-ALKYL-3-BETA-PHENYL ANALOGS OF COCAINE - SUBNANOMOLAR AFFINITY LIGANDS THAT SUGGEST A NEW PHARMACOPHOREMODEL AT THE C-2 POSITION, Journal of medicinal chemistry, 38(16), 1995, pp. 3086-3093
A series of 2 beta-alkyl-3 beta-phenyltropanes (i.e., the 2 beta-alkyl
analogues of the WIN series) were prepared as analogues of cocaine an
d tested for their ability to displace [H-3]mazindol binding and to in
hibit high-affinity dopamine uptake into striatal nerve endings (synap
tosomes). These 2 beta-alkyl analogues were readily prepared in optica
lly pure form starting from cocaine by proceeding through the 2 beta-p
henyl-bearing aldehyde 6 as a key intermediate. Wittig reaction of 6 w
ith the appropriate phosphorane and hydrogenation delivered the final
products. Ah new compounds with the exception of 8e were found to exhi
bit nanomolar or subnanomolar affinity for the cocaine binding site in
the rat striatum. These results are in apparent opposition to the bin
ding model previously proposed which suggests a hydrogen bond donor-ac
ceptor interaction to be present in the vicinity of the C-2 substituen
t. Taken together with our previous reports and recent findings from o
ther laboratories, we suggest a new pharmacophore model in which 2 bet
a-substituents lacking H-bond accepters enhance affinity to the bindin
g site through hydrophobic interactions. The new SAR data contained he
rein may be relevant to the design of possible cocaine antagonists.