Analysis of pain treatment drug targets and R&D tracks of key pharmaceutical companies

1.
Opioid receptors OR) and its antagonist opioid analgesic drugs are currently the most effective analgesic drugs, can be divided into weak and potent opioid drugs, weak drugs mainly include bucinnamine, tramadol and other drugs, strong drugs are hydrocodone, fentanyl, morphine
.
Opioid receptors have complex pharmacological effects due to their wide distribution
, diverse functions, and complex pharmacological effects.
Opioid receptors mainly include μ, κ, and δ
.
Pharmacological studies have shown that there are multiple isoforms of each receptor, such as μ1, μ2, μ3, κ1, κ2, δ1, δ2, etc
.
In general, morphine is an agonist of the three receptors of μ, κ, and δ, and the intensity of action on the three receptor subtypes is weakened
in turn.
1) The relationship between opioid receptor agitation and effect

2) Opioid peptide neurons in the analgesic mechanism can release internal opioid peptides (enkephalins), stimulate opioid receptors, inhibit acetylcholine through the G protein coupling mechanism, reduce calcium ion influx, increase potassium outflow, reduce the release of anterior membrane transmitters (P substances, etc.
), and hyperpolarize the postsynaptic membrane, thereby preventing the conduction and transmission of pain impulses and playing an analgesic role
.
Exogenous opioids can also act on opioid receptors to exert analgesic effects
.
3) Related new drugs on the market, August 2021 The US FDA approved the new drugs of Cara Therapeutics and Vifor Pharma Korsuva (difelikefalin) is marketed for the treatment
of chronic kidney disease-associated pruritus (CKD-aP) in adults receiving hemodialysis (HD).
The product is Kappa receptor agonist, the first FDA-approved CKD-aP therapeutics
.
4) Opioid receptor antagonists can antagonize Mμ, K, δ receptors, including naloxone, nalmephenol, naltrexone and other drugs
.
2、 Narcotic drugs 1) Classification of anesthetics

2) Anesthetic targets and marketed drugs

General anesthetics

A.
Propofol is a short-acting anesthetic widely used in clinical practice, GABAA receptor modulator, which may activate central GABA receptors and regulate the hypothalamic sleep pathway, and sleep can be produced within 40 seconds after intravenous injection, and enter anesthesia quickly and smoothly
.
May be metabolized in the liver mainly in combination with glucuronic acid, metabolites are excreted
in the urine.
It has an inhibitory effect on the respiratory system, and temporary respiratory arrest may occur; It also has an inhibitory effect on the circulatory system, and a decrease
in blood pressure may occur.
The anesthesia of this product recovers quickly, about 8 minutes, and nausea, vomiting and headache
can occur during the recovery period.
The usual state of maintenance is a single repeat injection or continuous intravenous infusion of propofol
.
For induction and maintenance
of general anesthesia.
Haisco intravenous anesthetic drug class 1 new drug cyclopofol injection was launched in
2020.
Compared with propofol, this product is used in smaller doses, has similar recovery times, produces fewer cases of injection pain, and has fewer
cardiovascular events.
B.
Etomidate Etomidate is a non-barbiturate short-acting intravenous anesthetic derived from
imidazoles.
The drug metabolism is fast, which is not only suitable for single use at the time of induction, but also suitable for intraoperative maintenance
.
The target of intravenous anesthetic is generally related to γ-aminobutyric acid, and the important target of the molecular mechanism of action of etomidate is the GABA-A receptor
.
It can also act on α-2β adrenergic receptors, thereby causing vasoconstriction and maintaining hemodynamic stability
.
Relying on milipid is not preferred, but has little effect on cardiovascular and respiratory circulation, high safety, especially suitable for patients with cardiovascular and respiratory diseases, patients with intracranial hypertension, as a substitute for propofol, adverse reactions are nausea, vomiting, cortisol inhibition and awakening are slower
than propofol.

Local anesthetics

It is currently recognized that local anesthetics block voltage-gated Na+ channels on nerve cell membranes channels), so that the conduction block, produce local anesthetic effect
.
The effect of local anesthetics is frequency and voltage dependent
.
Clinical applications: surface anesthesia, infiltration anesthesia, conduction anesthesia, subarachnoid anesthesia, epidural anesthesia, regional analgesia, etc
.
Among the 4 long-acting sustained-release preparations of bupivacaine that have been marketed abroad, they are liposomal Exparel, implantable Xaracoll, and gel Posimir and Zynrelef, of which Zynreref is a compound preparation
of bupivacaine and meloxicam.

Among them, bupivacaine/meloxicam sustained-release solution Zynreef, developed by Heron and approved by the FDA in May 2021, is infused into soft tissues or around the joints in the surgical area after bunionctomy, open inguinal hernia repair, and total knee replacement in adult patients, resulting in continuous analgesia for up to 72 hours
.
This product was approved by the European Union as early as September 2020 for the treatment of postoperative pain caused by small and medium-sized surgical wounds in adults
.
Zynerref is currently the only dual-acting long-acting local anesthetic analgesic
currently on the market.

Muscle relaxants

N2 choline receptor blockers, also known as skeletal muscle relaxants (skeletal muscular relaxants), can selectively act on N2 on the motor nerve endplate membrane receptors, which block the transmission of nerve impulses to skeletal muscle, leading to muscle relaxation
.
After the use of myosteorelaxants in clinical anesthesia, muscle relaxation is obtained by deepening general anesthesia to meet the requirements of
surgery.
Therefore, muscle relaxants have become an important adjunct to general anesthesia
.
In addition, muscle relaxants can be used in mechanically ventilated patients
.
Muscle relaxants are highly ionized, cannot pass through the membranous structure of cells, and have limited
volume of distribution.
3) Sedative-hypnotic drugs

benzodiazepine sedative-hypnotics,

Benzodiazepines are short-acting GABAa receptor agonists
.
It acts on GABAa receptors, which open cell channels and increase chloride influx, causing hyperpolarization of nerve cell membranes and inhibiting neuronal activity
.
The main mechanism of action is to act by strengthening the inhibitory neurotransmitter in the brain, namely γ-aminobutyric acid, which has anxiolytic, sedative hypnosis, interference with memory, amnesia, anticonvulsant, and antiskeletal muscle relaxation effects
。 Remizolam (BYFAVO) is a production of Acacia Developed by Pharma, approved by the FDA in 2020 and expanding its new portfolio for anesthesia, it is an extremely fast-acting/dysregulated anesthetic drug used to induce and maintain procedural sedation in adults undergoing procedures lasting 30 minutes or less, and its use can cause very rapid sedation and rapid postoperative recovery
.

non-benzodiazepine sedative-hypnotics,

Dexmedetomidine is optional α2-adrenergic agonist, with sedative, analgesic, anxiolytic, diuretic and other effects, differs in pharmacological properties - GABA receptor agonists (eg benzodiazepines and propofol), including greater arousal capacity, anti-inflammatory and analgesic effects, lack of respiratory depression and improved sleep
.
Unlike other sedative-hypnotics, the sedative effect of dexmedetopyrimidine is mainly to stimulate the α2 receptors of the blue spotal nucleus, producing an effect similar to normal sleep (intraoperative arousal is required in neurosurgery), and its analgesic effect mainly stimulates the α2 receptors of the blue spot nucleus, spinal cord, and peripherals, that is, naloxone can not block its analgesic effect
.
Dexmedetopyrimidine, unlike remifentanil, does not cause hyperalgesia
.
It can be combined with other analgesics during and after surgery, which can reduce the amount of analgesics by 50%.

On April 2022, the new drug Igalmi (dexmedetomidine) is the first and only oral hypoglossal membrane approved by the FDA for mild, moderate or severe agitation
in patients with schizophrenia or bipolar I or II disorder 。 3． Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of anti-inflammatory drugs that do not contain steroidal structures, such drugs include aspirin, acetaminophen, indomethacin, naproxen, naprodone, naprodone, diclofenac, ibuprofen, nimesulide, rofexib, celecoxib, etc.
, the class of drugs has anti-inflammatory, anti-rheumatic, analgesic, antipyretic and anticoagulant effects, and is widely used clinically for osteoarthritis, rheumatoid arthritis, a variety of fever and relief of various pain symptoms
.
NSAIDs produce moderate analgesia, mainly peripherally
.
Ineffective
against severe pain caused by various traumas and smooth muscular colic of internal organs.
It has a good
effect on chronic pain such as headache, joint muscle pain, toothache, etc.
Baudax Bio has developed Meloxicam Anjeso for intravenous injection with a new nanocrystalline technology to further improve the pain relief effect
.
In February 2020, Anjeso received FDA approval for the treatment of moderate to severe analgesia, becoming the first once-daily long-acting analgesic
.
Studies have shown that Anjeso can effectively reduce opioid use in patients, which has a positive impact
on reducing opioid use.
4.
Gabapentin voltage gate calcium channels (VGCC) is a group of voltage-gated ion channels found in the cell membrane of excitable cells, with permeability
to calcium ions.
At physiological or resting membrane potentials, VGCC is closed and activated at a depolarized membrane potential, and when VGCC is activated, calcium ions influx, activating calcium-sensitive potassium channels, muscle contraction, neuronal fire, hormone or neurotransmitter release, resulting in pain development
.
VGCC is composed of four different subunits: α1, α2δ, β1-4 and γ, of which α2δ subunits are divided into four different subtypes
of α2δ-1 (CACNA2D1), α2δ-2 (CACNA2D2), α2δ-3 (CACNA2D3) and α2δ-4 (CACNA2D4).
Gabapentins can act on the voltage gate calcium channel (VGCC) subunit α2δ (CACNA2D), inhibit the release of calcium-mediated neurotransmitters in the dorsal horn by binding to α2δ, blocking neuronal excitation and sensory signaling
.
At present, there are four drugs that have been marketed for CACNA2D, all of which belong to the gabapentin class, mainly used for the treatment of diabetic neuralgia and postherpetic neuralgia
.

In 2019, Mirogabalin (Mindray Bahrain Tarlige), which was approved for marketing in Japan, is a voltage gate α2δ-1 regulator (CACNA2D)
for the treatment of DPN, DNPN and PHN.
On October 27, 2022, according to the official website of the Center for Drug Evaluation (CDE) of the State Food and Drug Administration, the marketing application of HSK16149 capsules, a voltage gate α2δ-1 regulator of Haisco Pharmaceutical Group Co.
, Ltd.
, was accepted by CDE, and the main indication is diabetic peripheral neuralgia
.
Second, the analysis of the R&D pipeline of analgesics in key enterprises