Alazocine (developmental code name -10047), also known more commonly as ''N''-allylnormetazocine (NANM), is a
synthetic opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
analgesic of the
benzomorphan
Benzomorphan is a chemical compound that is the base for a series of drugs which variably act on the opioid kappa and sigma receptors, including the following compounds:
* 5,9-DEHB
* 8-CAC
* Alazocine
* Anazocine
* Bremazocine
* Butinazoc ...
family related to
metazocine, which was never marketed.
In addition to its opioid activity, the drug is a
sigma receptor
Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...
agonist, and has been used widely in
scientific research
The scientific method is an empirical method for acquiring knowledge that has characterized the development of science since at least the 17th century (with notable practitioners in previous centuries; see the article history of scientific m ...
in studies of this receptor.
Alazocine is described as a
potent analgesic,
psychotomimetic A drug with psychotomimetic (also known as psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms following the administrati ...
or
hallucinogen
Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorize ...
, and
opioid antagonist
An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.
Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the ...
.
Moreover, one of its
enantiomers was the first compound that was found to
selectively label
A label (as distinct from signage) is a piece of paper, plastic film, cloth, metal, or other material affixed to a container or product, on which is written or printed information or symbols about the product or item. Information printed ...
the
σ1 receptor, and led to the discovery and characterization of the receptor.
Pharmacology
Pharmacodynamics
Alazocine shows
stereoselectivity
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of ...
in its
pharmacodynamics
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...
.
The (–)-enantiomer is a non-selective and high-
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 ...
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
of the
μ-,
κ-, and
δ-opioid receptor
The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous lig ...
s (K
i = 3.0, 4.7, and 15 nM in
guinea pig
The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus '' Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ...
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
membranes) with very low affinity for the sigma σ
1 receptor (K
i = 1,800–4,657 nM in guinea pig brain membranes).
It acts as a moderate-
efficacy partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
of the κ-opioid receptor (K
i = 0.4 nM,
EC50 = 24 nM, and
Emax = 66% for (±)-alazocine against the
mouse receptor
transfected
Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to desc ...
in
HEK293 cells)
and as an
antagonist of the μ-opioid receptor (K
i = 1.15 nM for (±)-alazocine against the mouse receptor transfected in HEK293 cells).
It is also an
agonist of the δ-opioid receptor with far lower potency (K
i = not reported,
IC50 = 184 nM, and = 68% for (±)-alazocine against the mouse receptor transfected in HEK293 cells).
Conversely, the (+)-
stereoisomer
In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
has little affinity for the
opioid receptor
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin ...
s (K
i for 1,900 nM, 1,600 nM, and 19,000 nM for the μ-, κ-, δ-opioid receptors in guinea pig brain membranes) and instead is a selective and high-affinity
agonist of the σ
1 receptor (K
i = 48–66 nM in guinea pig brain membranes).
However, the (+)-enantiomer also shows moderate affinity for the
dizocilpine (MK-801) or
phencyclidine
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percept ...
(PCP) site of the
NMDA receptor (K
i = 587 nM in
rat brain membranes relative to 45 nM for the σ
1 receptor) and, hence, is an
uncompetitive NMDA receptor antagonist
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...
as well at higher concentrations.
As such, (+)-alazocine is only modestly selective as a ligand of the σ
1 receptor.
Both enantiomers of alazocine have very low affinity for the sigma
σ2 receptor (K
i = 13,694 nM and 4,581 nM for the (+)- and (–)-enantiomers, respectively, in rat brain membranes or rat
PC12 cells).
As such, due to its high affinity for the σ
1 receptor, (+)-alazocine can be used to distinguish between the two sigma receptor subtypes in scientific research, for instance in
radioligand binding assays.
Taken together, (–)-alazocine is a selective partial agonist of the κ-opioid receptor, antagonist of the μ-opioid receptor, and to a far lesser extent agonist of the δ-opioid receptor
with very low affinity for the sigma receptors, while (+)-alazocine is a selective agonist of the sigma σ
1 receptor and to a lesser (~10-fold) extent antagonist of the NMDA receptor with low affinity for the opioid and sigma σ
2 receptors.
History
Alazocine was one of the early members of the
benzomorphan
Benzomorphan is a chemical compound that is the base for a series of drugs which variably act on the opioid kappa and sigma receptors, including the following compounds:
* 5,9-DEHB
* 8-CAC
* Alazocine
* Anazocine
* Bremazocine
* Butinazoc ...
family of opioid analgesics to be investigated.
It was first described in the
scientific literature
: ''For a broader class of literature, see Academic publishing.''
Scientific literature comprises scholarly publications that report original empirical and theoretical work in the natural and social sciences. Within an academic field, scie ...
in 1961.
Its development resulted from
nalorphine
Nalorphine () (brand names Lethidrone, Nalline), also known as ''N''-allylnormorphine, is a mixed opioid agonist–antagonist with opioid antagonist and analgesic properties. It was introduced in 1954 and was used as an antidote to reverse op ...
(N-allylnormorphine), a potent analgesic and opioid antagonist with similar pharmacology which had been introduced in the mid-1950s.
Alazocine was found to produce strong psychotomimetic effects in humans, and it was not further developed for clinical use.
Subsequently, other benzomorphans, such as
pentazocine
Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such it is called an ...
(an ''N''-dimethylallylbenzomorphan),
cyclazocine
Cyclazocine is a mixed opioid agonist/antagonist related to dezocine, pentazocine and phenazocine. This family of opioid drugs is called the benzomorphans or benzazocines. It is a KOR agonist and MOR partial agonist, and also has high affinit ...
(an ''N''-cyclopropylmethylbenzomorphan), and
phenazocine (an ''N''-phenylethylbenzomorphan), were developed, and some have been marketed for use as analgesics.
The sigma σ
1 receptor was named in 1976 and (+)-alazocine was described as its prototypical ligand.
The receptor was initially thought to be an opioid receptor, and then was confused with the NMDA receptor for a time, but was ultimately distinguished from them both.
The psychotomimetic effects of alazocine and the other benzomorphans were initially attributed incorrectly to agonism of the σ
1 receptor; subsequent research established that the effects are in fact caused by agonism of the κ-opioid receptor and/or antagonism of the NMDA receptor.
The sigma σ
2 receptor was discovered and named in 1990, and was identified in part due to the dramatically reduced affinity of alazocine for the receptor relative to the σ
1 receptor (in contrast to non-selective ligands like
haloperidol
Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosi ...
,
ditolylguanidine, and
(+)-3-PPP, which show similar affinity for both subtypes).
References
{{Sigma receptor modulators
Allylamines
Analgesics
Benzomorphans
Delta-opioid receptor agonists
Dissociative drugs
Kappa-opioid receptor agonists
Mu-opioid receptor antagonists
NMDA receptor antagonists
Phenols
Sigma agonists