title: Design, synthesis and biological evaluation of multifunctional ligands targeting opioid and bradykinin 2 receptors.
abstract: We report here the design and synthesis of novel multifunctional ligands that act as (μ/δ) opioid agonists and bradykinin 2 receptor antagonists. These multifunctional ligands were designed to interact with the multiple receptors to show an enhanced analgesic effect, with no opioid-induced tolerance. We designed our multifunctional ligands based on the well-known second generation bradykinin 2 receptor antagonist Hoe 140 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH) and the opioid enkephalin analogues Tyr-DAla-Phe, Tyr-DAla-Gly-Phe and Tyr-Pro-Phe. We explored the conjugation of opioid pharmacophore to the Hoe 140 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH) in various positions with and without a linker. These bifunctional ligands showed very good binding affinity towards the both μ and δ opioid receptors. Among these bifunctional ligands 8, 11 and 12 showed excellent and balanced binding affinity at both μ and δ opioid receptors (0.5 nM, 2.0 nM; 0.3 nM, 2 nM; 2 nM and 3 nM), respectively. On the other hand these bifunctional ligands showed very weak and no binding affinity for rat brain bradykinin 2 receptors. Similarly, the Hoe 140 showed very low affinity (>10,000 nM and 9,000 nM) against [(3)H] BK binding in rat brain membranes and in HEK293 cells, respectively. In contrast, the Hoe 140 showed very good binding affinity in guinea pig ileum (0.43 nM) similar to that of previously reported. The bradykinin 2 receptors are known to be present in rat brain membrane, guinea pig ileum (GPI) and rabbit jugular vein. Previously the binding affinity of Hoe 140 for bradykinin 2 receptor was reported using guinea pig ileum. The above results suggest that the bradykinin 2 receptors present in rat brain membrane are a different sub type than the bradykinin 2 receptor present in guinea pig ileum (GPI).
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors: Srinivas
authors: S
authors: Deekonda
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: David
authors: D
authors: Rankin
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Peg
authors: P
authors: Davis
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Josephine
authors: J
authors: Lai
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Frank
authors: F
authors: Porreca
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA. Electronic address: hruby@email.arizona.edu.
authors: Victor J
authors: VJ
authors: Hruby
mesh_terms: D000818:Animals; D065094:Bradykinin B2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D011957:Receptors, Opioid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D008024:Ligands; D009842:Oligopeptides; D043782:Receptor, Bradykinin B2; D011957:Receptors, Opioid
keywords: Bradykinin receptor; Multifunctional ligand; Opioid receptors; Pain