biphalin and Pain

Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases.

Topics: Analgesics; Analgesics, Opioid; Enkephalins; Morphine; Opioid-Related Disorders; Pain; Receptors, Opioid

Seldom in medicinal chemistry does one ligand present the ability to study two separate phenomena in a pharmacological process. The discovery of biphalin with other homodimeric ligands has given scientists a tool that not only explores how to increase the efficacy of the ligand, but also explore the possible interactions of hetero and homo dimerization of the receptors themselves. As a straight ligand, biphalin has allowed scientists to increase efficacy by direct modification of the residues to affect the message-address interactions with receptors. This led to the exploration of ligand linkers to increase efficacy and it was this modification of the linkers led to discoveries that suggested dimerization of receptor system occurs as a secondary modulation of signal transduction. Even more recently, exploration of the advances in linkers through the discovery of bitopicity seems to modulate the actual receptors to increase the binding and signal transdcution of the ligand. This is accomplished by possible slight conformational changes in the receptors before binding of the ligand located at the end of the linker. These advances were made by the work of the late Prof. Andrzej W. Lipkowski. This review gives the foundation of biphalin and in turn celebrates the contributions of Prof. Lipkowski made in this area.

Topics: Dimerization; Enkephalins; Humans; Ligands; Pain; Protein Binding; Receptors, Opioid; Structure-Activity Relationship

Topics: Analgesics; Drug Delivery Systems; Drug Design; Enkephalins; Humans; Microspheres; Narcotics; Pain; Polymers; Substance P

Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for μ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands,

Topics: Administration, Intravenous; Analgesics, Opioid; Animals; CHO Cells; Cricetulus; Female; Humans; Infusions, Subcutaneous; Male; Mice; Models, Molecular; Opioid Peptides; Pain; Peptides, Cyclic; Receptors, Opioid

Biphalin, a synthetic opioid octapeptide with a palindromic sequence has high analgesic activity. Biphalin displays a strong affinity for μ and δ-opioid receptors, and a significant to κ-receptor. The paper reports the synthesis of novel analogs of biphalin containing β(3)-homo-amino acid residues at the 4,4' positions and a hydrazine or 1,2-phenylenediamine linker. The potency and selectivity of the peptides were evaluated by a competitive receptor-binding assay in rat brain homogenate using [(3)H]DAMGO (a μ ligand) and [(3)H]DELT (a δ ligand). Analogs with β(3)-h-p-NO2Phe in positions 4 and 4' are the most active compounds. Selectivity depends on the degree of freedom between the two pharmacophore moieties. Analogs with a hydrazine linker show noticeable binding selectivity to μ receptors (IC50(μ)=0.72nM; IC50(δ)=4.66nM), while the peptides with a 1,2-phenylenediamine linker show slight δ selectivity (IC50(μ)=10.97nM; IC50(δ)=1.99nM). Tyr-d-Ala-Gly-β(3)-h-p-NO2PheNHNH-β(3)-h-p-NO2Phe (1) and (Tyr-d-Ala-Gly-β(3)-h-p-NO2PheNH)2 (2) produced greater antinociceptive effect compared to morphine after i.t. administration.

Topics: Amino Acids; Analgesics, Opioid; Animals; Enkephalins; Male; Pain; Peptides; Protein Binding; Rats; Rats, Wistar; Receptors, Opioid, delta

Biphalin [(Tyr-D-Ala-Gly-Phe-NH-)2 ] is an octapeptide with mixed μ/δ opioid activity. Its structure is based on two identical enkephalin-like portions linked "tail-to-tail" by a hydrazine bridge. This study presents the synthesis and in vitro and in vivo bioassays of two biphalin analogs that do not present the toxicity connected with the presence of the hydrazine moiety and are able to elicit a higher antinociceptive effect than biphalin.

Topics: Analgesics, Opioid; Animals; Cells, Cultured; Enkephalins; Male; Molecular Structure; Pain; Protein Binding; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu

Biphalin is an opioid linear octapeptide, which displays a broad affinity for all opioid receptors (μ, δ and κ), as well as exceptionally high antinociceptive activity. AM 94 is a biphalin analog and a selective agonist at μ and δ opioid receptors. This study investigated the antinociceptive profile of AM 94. All antinociception evaluations were made in adult male rats using the hot-plate test. AM 94 proved to induce greater and longer antinociception compared to biphalin following intracebroventricular (1 nmol/kg) and intravenous administration (1200 nmol/kg) as evaluated by % maximum possible effect (M.P.E.), when administered intracerebroventricularly and intravenously and sustained analgesia up to 210 min. The antinociceptive activities of biphalin and AM 94 were antagonized by naloxone (10mg/kg intraperitoneally). Our data suggest that AM 94 could be regarded as a novel pharmacologically active opioid compound for eliciting potent and sustained analgesia after central and peripheral administration.

Topics: Analgesics; Animals; Disease Models, Animal; Enkephalins; Injections, Intravenous; Injections, Intraventricular; Male; Naloxone; Narcotic Antagonists; Oligopeptides; Pain; Piperazines; Rats; Rats, Wistar; Time Factors

Intraspinal drug delivery, based on the concept of controlling pain by delivering drug to a nociceptive target rich in opioid and other relevant receptors is increasingly used clinically. The therapeutic ratio for opioids or other centrally acting agents is potentially greater if they are administered intrathecally (i.t.) than outside the central nervous system (CNS). The present study was designed with the ultimate goal of formulating a controlled release system for intrathecal analgesia characterized by effectiveness, rapid onset and few side effects for chronic pain control. A biodegradable copolymer poly(L-lactide-co-glycolide) (PLGA) was used to prepare a rod-shaped drug delivery system containing hydromorphone (HM), bupivacaine (BP), both HM and BP, or biphalin (BI). In vitro drug release kinetics of these systems showed a zero-order release rate for HM and BP from PLGA (85:15) rods. Drug-loaded rods were implanted i.t. Control groups received only placebo implants. Measurement of analgesic efficacy was carried out with tail flick and paw-withdrawal tests. In vivo studies showed potent, prolonged analgesia in comparison to controls for all active treatments. Analgesic synergy was observed with HM and BP. With further refinements of drug release rate, these rods may offer a clinically relevant alternative for intrathecal analgesia.

Topics: Analgesics; Animals; Bupivacaine; Drug Delivery Systems; Drug Implants; Enkephalins; Hydromorphone; Injections, Spinal; Lactic Acid; Male; Pain; Pain Measurement; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rats; Rats, Sprague-Dawley

Previous studies of structure-activity of biphalin defined fragments which expressed the full biological potency of the parent compound. The most simple fragment was Tyr-D-Ala-Gly-Phe-NH-NH<--X, where X=Phe, but it also could be other hydrophobic amino acids. This paper presents data that replacement of the phenylalanine with a dansyl (X=DNS) groups gives an analogue (AA2016) that fully preserves the high affinity of the initial analogue for both mu and delta opioid receptors. In the tail flick test in rats, intrathecal injection of the compound produces strong antinociception, comparable to the parent biphalin. Because AA2016 contains a strong fluorescent group, it can be a very useful tool for prospective studies in vivo, including biological barrier permeability, tissue distribution, metabolism and receptor-ligand complex formation.

Topics: Analgesia; Analgesics; Animals; Dansyl Compounds; Enkephalins; Fluorescent Dyes; Male; Pain; Phenylalanine; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu

Intrathecal injection of 0.25 micrograms of undecapeptide substance P antagonist (SPA) produced transient antinociception with a peak effect at 5 min. Increasing the SPA dose resulted in neurotoxicity. Intrathecal injection of the opioid peptide biphalin (BIP) produced antinociception for over 3 hrs without neurotoxicity. Co-administration of SPA (at subtoxic doses) increased BIP's antinociceptive effect. Naltrexone reversed analgesia due to BIP alone as well as after BIP+SPA.

Topics: Analgesics; Animals; Drug Synergism; Enkephalins; Injections, Spinal; Male; Naltrexone; Pain; Pain Measurement; Rats; Rats, Wistar; Substance P