Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide

被引:62
作者
Khalil, EM
Ojala, WH
Pradhan, A
Nair, VD
Gleason, WB
Mishra, RK
Johnson, RL [1 ]
机构
[1] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Ctr Biomed Engn, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
[4] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON L8N 3Z5, Canada
关键词
D O I
10.1021/jm980525q
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In the present study, the synthesis of the 5.5.6. and 5.6.5. spiro bicyclic lactam PLG peptidomimetics, compounds 3 and 4, respectively, was undertaken. These peptidomimetics were designed to examine the following: (1) the effect that changing the size of the thiazolidine and lactam ring systems would have on the ability of these systems to mimic the type-II beta-turn and (2) the effect that these structural perturbations would have on the ability of the peptidomimetics to modulate dopamine receptors. Through the use of the [H-3]spiroperidol/N-propylnorapomorphine (NPA) dopamine D-2 receptor competitive binding assay, 3 and 4, at a concentration of 100 nM, decreased the dissociation constant of the high-affinity state of the dopamine receptor for the agonist. These effects were observed when either Gpp(NH)p was absent or present and they were comparable to those produced by PLG at a concentration of 1 mu M. Peptidomimetics 3 and 4 also increased the percentage of D-2 receptors that existed in the high-affinity state. Even with Gpp(NH)p present, 3 and 4 were able to return the R-H/R-L ratios to values observed in the respective controls where Gpp(NH)p was absent. Furthermore, both peptidomimetics were able to attenuate the Gpp(NH)p-induced shift to the low-affinity state to a greater extent than PLG. Peptidomimetics 3 and 4 were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism, and each affected the rotational behavior in a bell-shaped dose-response relationship producing increases of 95 +/- 31% (0.01 mg/kg, ip) and 88 +/- 14% (0.001 mg/kg, ip), respectively. In comparison, the previously reported 5.5.5. spiro bicyclic lactam 2 increased rotational behavior by 25 +/- 11% (0.01 mg/kg, ip).
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页码:628 / 637
页数:10
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