Identification of potent and highly selective chiral tri-amine and tetra-amine μ opioid receptors ligands: An example of lead optimization using mixture-based libraries

Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors

“…28−31 For instance, screening of permethylated chiral tetramines derived from resin-bound tripeptides identified permethylated YYF, a high affinity (0.5 nM), selective MOR antagonist. 32 Likewise, the screening of a series of bicyclic guanidines derived from reduced tripeptides led to the identification of a bicyclic guanidine with good affinity and selectivity for the KOR. 26 Recently, we reported the identification of two novel, potent, low-liability antinociceptive compounds from the direct in vivo screening of a large mixturebased combinatorial library of pyrrolidine bis-cyclic guanidines derived from resin bound, proline containing acylated tetrapeptides, 31 further suggesting the therapeutic potential of peptidomimetics.…”

“…Finally, given that peptides generally cross the blood−brain barrier and penetrate the CNS poorly after peripheral administration, it was theorized that peripherally selective peptidomimetic opioid agonists would demonstrate analgesia without the liabilities associated with the activation of opioid receptors in the CNS. 32 Continuing with our efforts toward the generation of heterocyclic peptidomimetics from modified resin bound peptides, we report the parallel synthesis of fused diimidazodiazepines, from reduced tripeptides. The diimidazodiazepine compounds were subjected to initial pharmacological screening in vitro for opioid receptor affinity with radioligand competition binding assays.…”

Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput “Unbiased” Screening Campaign

“…It has been reported that the pyrrolidine bis-cyclic guanidine template was used to identify novel compounds with antinociceptive activity (lasting up to 5 h) and possesses antimicrobial activity to drug-resistant Gram-positive pathogens (Figure ). , In addition, both tri- and tetra-amine templates have been used to identify potent, MOR-selective compounds . The exact structures and side-chain substitutions were different within the scaffold mixtures and devoid of reactive functionalities.…”

“…63,64 In addition, both tri-and tetra-amine templates have been used to identify potent, MOR-selective compounds. 65 The exact structures and side-chain substitutions were different within the scaffold mixtures and devoid of reactive functionalities. This indicates that these templates/ scaffolds are not simply pan-assay interference compounds (PAINS) that can lead to false positives.…”

Endogenous opiates and behavior: 2009

“…Bivalent ligands containing homo-and heterodimeric pharmacophores at mu, delta and kappa opioid receptors were developed and synthesized in an in vitro assay (895). Potent and highly selective chiral tri-amine and tetra-amine MOR ligands were identified by lead optimization using mixture-based libraries (831). Opioid and CCK receptors also have overlapping pharmacophores required for binding affinity and biological activity (8).…”