Bivalent ligands of opioid receptors

Opioids are the oldest drugs know to humanity, which have been and continue to be used for the treatment of chronic pain. Unfortunately they have a large numbers of side effects [1–6]. Three main types of opioid receptors μ (MOR), δ (DOR) and κ (KOR) are known [8]. The ORL1 receptor was classified as the fourth member of opioid receptor family [9]. Opioid receptors can form homodimers and the following heterodimers: DOR-KOR, DOR-MOR and KOR-MOR [13c,d,f, 14]. Specially designed ligands which are able to penetrate the BBB are used to study physiological consequences of opioid receptor homo- and heterodimerization, and as new analgesics. Bivalent ligands are defined as compounds that contain two pharmacophoric units, an appropriately designed spacer to separate and define the two pharmacophores, and a linker unit to connect the pharmacophores, to the spacer (Fig. 1) [16]. The affinity of a ligand to its target depends on its fundamental kinetic association and dissociation rate constants (Scheme 1) [24]. Bivalent ligands interacting with the opioid receptors have been divided into three groups: nonpeptide, peptide- nonpeptide and peptide homo- or heterodimers. Nonpeptide bivalent ligands (4–21, 27–41 and 44–45) containing different pharmacophores (selective opioid agonists or/and antagonists) connected with designed linkers have potent analgesic properties [25–34]. Compound 35 may be useful in the treatment of opioid dependence. Studies of peptide-nonpeptide ligands, which are a combination of “address” segments of endogenous opioid peptides and selective alkaloid ligand (47–50) indicate that peptide part of the analogues can modulate the receptor selectivity of the attached alkaloid pharmacophores [35]. Series of peptide-nonpeptide ligands containing different classes of opioid peptides and fentanyl (52–86) were synthesized and tested for binding affinity to μ and δ opioid receptors [38–40]. Good opioid affinity and antinociceptive activity of some of the obtained bivalent ligands (57, 61, 63) suggesting that a novel class of analgesics can be further developed utilizing this approach. Among homobivalent ligands the most important is biphalin 87 and its analogues (88–124) [41–53]. Analgesic potency of the most active ligand 112 is greater than parent peptide (biphalin) and morphine