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3-Aryl-2-(3'-substituted-1',2',4'-oxadiazol-5'-yl)tropane analogues of cocaine: affinities at the co

3-Aryl-2-(3'-substituted-1',2',4'-oxadiazol-5'-yl)tropane analogues of cocaine: affinities at the co

  1. Anonymous
    Carroll FI, Gray JL, Abraham P, Kuzemko MA, Lewin AH, Boja JW, Kuhar MJ. 3-Aryl-2-(3'-substituted-1',2',4'-oxadiazol-5'-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters. Journal of Medicinal Chemistry. 1993 Oct 1;36(20):2886-90. PMID 8411004

    Previous studies have shown that 3/3-(substituted phenyl)tropan-2~-carboxyliacc id esters possess
    high affinity for the cocaine binding site on the dopamine transporter both in vitro and in vivo
    and inhibit dopamine uptake in vitro. Since 1,2,4-oxadiazoles are excellent bioisosteres of ester
    groups, we have prepared several 3/3-(substituted phenyl)-2/3-(3-~ubstitute1d’ ,2’,4’-oxadiazol-5’-
    . y1)tropanes (5b-h) and all four stereoisomers of (1R,5S)-3 phenyl-2-(3-methyl-l’,2’,4’-oxadiazol-
    5’-yl)tropane (5a and 6-8). The 3a-phenyl-2a-(3’-methyl-1’,2’,4’-oxadiazolies)o mer 7 was prepared from a stereoselective addition of phenyllithium to (1R,5S)-2-(3’-methy1-1’,2’,4’-oxadizo1-5-y1)-8-
    methyl-8-azabicyclo[3.2.lloct-2-en(1e 1). The binding affinities for 5a-h and 6-8 at the dopamine,
    serotonin, and norepinephrine transporters were obtained. In general these bioisosteres showed
    potencies for the dopamine transporter similar to those of their parent esters. 3/3-(4’-Chlorophenyl)-
    2~-(3’-phenyl-1’,2’,4’-oxadiazol-5’-yl)tropan(e5 d) was the most potent analogue with an I CW of
    1.62 nM. However, 3/3-(4’-chlorophenyl)-2/3-(3’-methoxyphenyl-l’,2’,4’-oxadiazol-5’-yl)trop(a5nee) with an ICs0 of 1.81 nM was the most selective analogue for the dopamine transporter showing NE/DA and 5-HT/DA ratios of 461 and 186, respectively. The cis- and trans-3a-phenyl-2-(3’-
    methyl-l’,2’,4’-oxadiazol-5’-yl)tropanes (7 and 8), which exist in a boat conformation, have IC60
    values only slightly greater than that of the 3/3,2/3-isomer (5a) which possesses the cocaine
    stereochemistry.