Allosteric modulation of the dopamine D2 receptor by Pro-Leu-Gly-NH2 peptidomimetics constrained in either a polyproline II helix or a type II beta-turn conformation.
Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH(2). The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor.
Raghavan
Bhooma
B
Department of Medicinal Chemistry, University of Minnesota, SE, Minneapolis, Minnesota 55455, USA.
Skoblenick
Kevin J
KJ
Bhagwanth
Swapna
S
Argintaru
Niran
N
Mishra
Ram K
RK
Johnson
Rodney L
RL
D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D003342:Corpus Striatum / Q000378:metabolism; D018360:Crystallography, X-Ray; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D009075:MSH Release-Inhibiting Hormone / Q000737:chemistry*; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C117658:1-(2-pyrrolidinylcarbonyl)-5'-oxospiro(pyrrolidine-2,6'-thiazolidino(3,2-a)piperidine)-3'-carboxamide; D006574:Heterocyclic Compounds, 2-Ring; D009842:Oligopeptides; D010455:Peptides; C514790:Pro-Pro-Pro-NH2; D017448:Receptors, Dopamine D2; D013141:Spiro Compounds; D053778:Thiazolidines; C011083:polyproline; D009075:MSH Release-Inhibiting Hormone