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Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [35S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01's properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use. [ABSTRACT FROM AUTHOR]

Chemical stability is one of the main problems during the discovery and development of potent drugs. When ignored, it may lead to unreliable biological and pharmacokinetics data, especially regarding the degradation of products' possible toxicity. Recently, two biologically active drug candidates were presented that combine both opioid and neurotensin pharmacophores in one entity, thus generating a hybrid compound. Importantly, these chimeras are structurally similar except for an amino acid change at position 9 of the peptide chain. In fact, isoleucine (C6H13NO2) was replaced with its isomer tert-leucine. These may further lead to various differences in hybrids' behavior under specific conditions (temperature, UV, oxidative, acid/base environment). Therefore, the purpose of the study is to assess and compare the chemical stability of two hybrid peptides that differ in nature by way of one amino acid (tert-leucine vs. isoleucine). The obtained results indicate that, opposite to biological activity, the substitution of tert-leucine into isoleucine did not substantially influence the compound's chemical stability. In fact, neither hydrolysis under alkaline and acidic conditions nor oxidative degradation resulted in spectacular differences between the two compounds—although the number of potential degradation products increased, particularly under acidic pH. However, such a modification significantly reduced the compound's half-life from 204.4 h (for PK20 exposed to 1M HCl) to 117.7 h for [Ile9]PK20. [ABSTRACT FROM AUTHOR]

Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures. [ABSTRACT FROM AUTHOR]

One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid 'second' targets included proteins as diverse as imidazoline I2 binding sites, CB1 cannabinoid receptor, NK1 tachykinin receptor, D2 dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ1 receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work. [ABSTRACT FROM AUTHOR]