Design, Synthesis, X-ray Analysis, and Dopamine Receptor-Modulating Activity of Mimics of the "C5" Hydrogen-Bonded Conformation in the Peptidomimetic 2-Oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide

Abstract

3(R)-(7a(S)-Hexahydro-1-oxo-3,3-dimethyl-1H-pyrrolo[1,2-c]imidazol-2-yl) - oxo-1-pyrrolidine-acetamide (2) and 3(R)-[1-(2,5-dioxopyrrolidino[3,4-c]piperazino)]-2-oxo-1- pyrrolidineacetamide (3) were designed and prepared as mimics of the "C5" hydrogen-bonded structure found in the crystal structure of 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide (1). Both compounds effectively restrict the psi 1 torsional angle to very near the value found in the X-ray structure of 1 as seen in the X-ray crystallographic determination of 2 and methyl 3(R)-[1-(2,5-dioxopyrrolidino[3,4-c]piperazino)]-2-oxo-1- pyrrolidineacetate (11), a diketopiperazine intermediate in the synthesis of 3. These analogs were tested for their ability to enhance the binding of the dopamine D2 receptor agonist N-propylnorapomorphine (NPA) in the absence and presence of 5'-guanylylimidodiphosphate (Gpp(NH)p). Both compounds enhanced [3H]-NPA binding in a dose-dependent manner by increasing both the binding affinity of the agonist and the number of high-affinity sites available for binding. Both 2 and 3 also attenuated the Gpp(NH)p-induced conversion of D2 receptor high-affinity states to the low-affinity states.

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

“…During research to identify new dopamine D 2 receptor modulating agents, Baures and co-workers demonstrated the bioisosteric relationship existing between the amide bond ( l -prolyl- l -leucylglycinamide 132 ) and diketopiperazine (DKP) functionalities ( 133 , 134 , and 135 ) (Figure ). Earlier, these authors have reported that 132 modulates the dopamine D 2 receptor by increasing the affinity of the receptor for agonists. , Compound 133 was designed previously to mimic an N-terminal “C5” conformation involving an intermolecular hydrogen bond between the prolyl nitrogen and the lactam NH in an analog of parent 132 (structure not shown), which possessed better activity in a number of pharmacological assays. , In order to further explore SAR, the DKP containing compounds 134 and 135 were designed in which a “C5” conformational mimic was incorporated into the parent structure ( 132) and a bicyclic lactam moiety was assimilated (present in a potent 132 analog, structure not shown), respectively . The dopamine receptor modulation ability of 134 and 135 was assessed by measuring activity in a [ 3 H]­spiro-peridol/ N -propylnorapomorphine (NPA) D 2 receptor competitive binding assay in the presence as well as absence of 5′-guanylyl imidodiphosphate (Gpp­(NH)­p); K H and K L represent the inhibitor constant ( K i ) of agonist calculated for the high- and low-affinity components of the [ 3 H]­spiroperidol binding, respectively (Figure ).…”

“…175 Earlier, these authors have reported that 132 modulates the dopamine D 2 receptor by increasing the affinity of the receptor for agonists. 176,177 Compound 133 was designed previously 178 to mimic an N-terminal "C5" conformation involving an intermolecular hydrogen bond between the prolyl nitrogen and the lactam NH in an analog of parent 132 (structure not shown), which possessed better activity in a number of pharmacological assays. 179,180 In order to further explore SAR, the DKP containing compounds 134 and 135 were designed in which a "C5" conformational mimic was incorporated into the parent structure (132) and a bicyclic lactam moiety was assimilated (present in a potent 132 analog, structure not shown), respectively.…”

Allosteric Modulation of the Dopamine D2 Receptor by Pro-Leu-Gly-NH2 Peptidomimetics Constrained in Either a Polyproline II Helix or a Type II β-Turn Conformation

“…PLG increases the affinity of the high-affinity state of the dopamine receptor for agonists and it increases the ratio of the dopamine receptor in the high-affinity state, which is coupled to G-proteins 1,4. PLG also prevents and reverses drug-induced dopamine receptor super sensitivity caused by dopamine receptor antagonists 5–7…”

Discovery of New Potent Positive Allosteric Modulators of Dopamine D2 Receptors: Insights into the Bioisosteric Replacement of Proline to 3-Furoic Acid in the Melanostatin Neuropeptide

“…However, the PAM activity observed for 4a and 6a demonstrates that 3-furoyl derivatives may compensate for the absence of a basic “N-terminal” by engaging as a hydrogen bond acceptor. The successful use of a 3-furoyl moiety as a Pro surrogate in the MIF-1 structure not only establishes Pro as a suitable residue for chemical derivatization but also raises the debate about the possibility of MIF-1 to adopt different bioactive conformations other than the type II β-turn. ,,,− …”