Synthesis and dopamine receptor modulating activity of substituted bicyclic thiazolidine lactam peptidomimetics of L-prolyl-L-leucyl-glycinamide.
6-Substituted bicyclic thiazolidine lactam peptidomimetics of Pro-Leu-Gly-NH(2) (1) were synthesized to test the hypothesis that incorporation of a hydrophobic side chain into the bicyclic thiazolidine lactam scaffold would further enhance the dopamine receptor modulating activity of such peptidomimetics. The substituents employed were the isobutyl, butyl, and benzyl groups to give peptidomimetics 3-5, respectively. These peptidomimetics were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism and were compared with the unsubstituted bicyclic thiazolidine lactam Pro-Leu-Gly-NH(2) peptidomimetic 2. Peptidomimetics 3-5 each affected rotational behavior in a bell-shaped dose-response relationship producing maximal increases of 44% (1 microgram/kg,ip), 56% (0.1 microgram/kg,ip), and 30% (1 microgram/kg, ip), respectively. In comparison, unsubstituted peptidomimetic 2 increased rotational behavior by only 23% at a dose of 0.1 microgram/kg, ip.
Khalil
E M
EM
Department of Medicinal Chemistry, The Biomedical Engineering Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Pradhan
A
A
Ojala
W H
WH
Gleason
W B
WB
Mishra
R K
RK
Johnson
R L
RL
D000818:Animals; D018360:Crystallography, X-Ray; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009075:MSH Release-Inhibiting Hormone / Q000737:chemistry*; D008297:Male; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines
C120795:6-((2-pyrrolidinylcarbonyl)amino)-6-(2-methylpropyl)-5-oxo-(5H)-pyrrolo(2,1-b)thiazolidine-3-carboxamide; C120797:6-((2-pyrrolidinylcarbonyl)amino)-6-benzyl-5-oxo-(5H)-pyrrolo(2,1-b)thiazolidine-3-carboxamide; C120796:6-((2-pyrrolidinylcarbonyl)amino)-6-butyl-5-oxo-(5H)-pyrrolo(2,1-b)thiazolidine-3-carboxamide; D015259:Dopamine Agents; D007769:Lactams; D011759:Pyrrolidines; D013844:Thiazoles; D053778:Thiazolidines; D016627:Oxidopamine; D009075:MSH Release-Inhibiting Hormone