Bi- or multifunctional opioid peptide drugs

Abstract

Strategies for the design of bi-or multifunctional drugs are reviewed. A distinction is made between bifunctional drugs interacting in a monovalent fashion with two targets and ligands containing two distinct pharmacophores binding in a bivalent mode to the two binding sites in a receptor heterodimer. Arguments are presented to indicate that some of the so-called "bivalent" ligands reported in the literature are unlikely to simultaneously interact with two binding sites. Aspects related to the development of bi-or multifunctional drugs are illustrated with examples from the field of opioid analgesics. The drug-like properties of the tetrapeptide Dmt 1 [DALDA] with triple action as a μ opioid agonist, norepinephrine uptake inhibitor and releaser of endogenous opioid peptides to produce potent spinal analgesia are reviewed. Rationales for the development of opioid peptides with mixed agonist/antagonist profiles as analgesics with reduced side effects are presented. Progress in the development of mixed μ opioid agonist/δ opioid antagonists with low propensity to produce tolerance and physical dependence is reviewed. Efforts to develop bifunctional peptides containing a μ opioid agonist and a cholecystokinin antagonist or an NK1 receptor antagonist as analgesics expected to produce less tolerance and dependence are also reviewed. A strategy to improve the drug-like properties of bifunctional opioid peptide analgesics is presented.

Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons

“…Therefore, the antiserum primarily recognizes DOR1, although an excessive amount of antiserum might generate nonspecific binding. Using the antibodies above at a dilution of 1:30,000, we found that DORs were present in peptidergic and vanilloid receptor type 1-ir small neurons ( Interestingly, we found the presence of DORs on the cell surface in ∼14% of DRG neurons when we tested another antibody, now against DOR1 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] (1:60,000-120,000; Alomone) that also recognized Myc-DOR1 expressed in HEK293 cells ( Fig. 3 H and I and Fig.…”

“…These patterns are shown by immunostaining of both exogenously expressed Myc-DOR1 and endogenous DORs using antibodies against DOR1 3-17 or DOR1 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] . Thus, these antibodies against different N-terminal regions of DOR1 might recognize DORs in different states of activation, conformation, glycosylation, and/or palmitoylation (41)(42)(43)(44).…”

“…Gomes et al (6) reported that DORs interact with MORs in membranes purified from the spinal cord, negatively regulating MOR activity. Moreover, antinociceptive tolerance to morphine can be reduced by pharmacological blockade (1,2) or genetic interruption of the DOR system (8,9,19). Therefore, further study of the mechanism underlying DORmediated regulation of MOR activity could clarify the role of DORs in the modulation of morphine-induced antinociception and tolerance and may help to improve opioid analgesia.…”

“…Adult rats, mice, and Oprd1 exon 1-deleted mice were fixed. Cryostat sections of L4 and L5 DRGs and spinal cord segments were processed for immunofluorescence staining (13) with Rb anti-DOR1 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] (1:2,000-1:60,000; DiaSorin and 1:4,000-1:60,000; Neuromics), Rb anti-DOR1 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] (1:30,000-1:120,000; Alomone), Rb anti-DOR1 358-372 (1:1,000-1:2,000; Lifespan Biosciences), Rb anti-MOR (1:1,000; Neuromics); guinea pig anti-SP (1:500; Neuromics), and mouse anti-CGRP (1:1,000; Biogenesis) antibodies. IB4-labeling was carried out with fluorescein-labeled GSL I-IB4 (1:200).…”

“…However, their chronic use may lead to the development of antinociceptive tolerance. Blockade of δ-opioid receptors (DORs) results in enhanced morphine analgesia and reduced tolerance (1,2), suggesting interaction between DORs and MORs in the pain pathway (3)(4)(5)(6). This idea is further supported by findings that morphine tolerance can be reduced by preventing DOR phosphorylation (7) or by deleting exon 2 of the DOR1 gene (Oprd1) (8) or the preproenkephalin gene (Penk1) (9).Therefore, a further understanding of the interaction between the MOR and DOR systems is essential in attempts to improve pain treatment by means of opioid mechanisms.…”