Metkefamide (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

; LY-127,623), or metkephamid acetate (

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), but most frequently referred to simply as metkephamid, is a synthetic opioid pentapeptide and derivative of etnkephalin with the

amino acid sequence Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

Tyr-D-Ala-Gly-Phe-(''N''-Me)-Met-NH₂. It behaves as a potent agonist of the δ- and

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

s with roughly equipotent

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

, and also has similarly high affinity as well as subtype-selectivity for the κ₃-opioid receptor. Despite its peptidic nature, upon systemic administration, metkefamide rapidly penetrates the blood-brain-barrier and disperses into the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

where it produces potent, centrally-mediated analgesic effects, of which have been shown to be dependent on activity at both the μ- and δ-opioid receptors. In addition, on account of modifications to the N- and C-terminals, metkefamide is highly stable against

proteolytic degradation Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...

relative to many other opioid peptides. As an example, while its parent peptide, etnkephalin, has an ''in vivo''

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

of merely seconds, metkefamide has a half-life of nearly 60 minutes, and upon

intramuscular administration Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

, has been shown to provide

pain relief Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professional ...

that lasts for hours. Likely on account of its δ-opioid activity,

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s have found metkefamide to possess less of a tendency for producing many of the undesirable

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s usually associated with conventional opioids such as respiratory depression, tolerance, and

physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certai ...

. However, it has been shown to cause some additional side effects that are considered unusual for standard opioid analgesics like sensations of heaviness in the extremities and

nasal congestion Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels. Background In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathin ...

—though these were not considered to be particularly distressing—and it has also been shown to raise the seizure threshold in animals. In any case, clinical development was not further pursued after phase I clinical studies and metkefamide never reached the pharmaceutical market.

References

{{Opioidergics Analgesics Opioid peptides

See also

References