Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide.
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 [3H]spiroperidol/N-propylnorapomorphine (NPA) dopamine D2 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 microM. Peptidomimetics 3 and 4 also increased the percentage of D2 receptors that existed in the high-affinity state. Even with Gpp(NH)p present, 3 and 4 were able to return the RH/RL 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).
Department of Medicinal Chemistry and The Biomedical Engineering Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
E M
EM
Khalil
W H
WH
Ojala
A
A
Pradhan
V D
VD
Nair
W B
WB
Gleason
R K
RK
Mishra
R L
RL
Johnson
D000818:Animals; D001667:Binding, Competitive; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009075:MSH Release-Inhibiting Hormone / Q000737:chemistry*; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines; D014961:X-Ray Diffraction
C117658:1-(2-pyrrolidinylcarbonyl)-5'-oxospiro(pyrrolidine-2,6'-thiazolidino(3,2-a)piperidine)-3'-carboxamide; C117657:1-(2-pyrrolidinylcarbonyl)tetrahydro-6'-oxospiro(pyrrolidine-2,7'-(5'H)-pyrrolo(2,1-b)thiazine)-4'-carboxamide; D015259:Dopamine Agents; D007769:Lactams; D017448:Receptors, Dopamine D2; D013141:Spiro Compounds; D013843:Thiazines; D013844:Thiazoles; D053778:Thiazolidines; D009075:MSH Release-Inhibiting Hormone