Overview Of The Different Opioid Receptors And Their Subtypes

Opioid receptors are distributed widely in brain and found in spinal cord and peripheral sensory and autonomic nerves. There are the three well-characterized members of the opioid receptor family, designated by the Greek symbols 8, k and The more recently discovered ORL1 receptor is placed with this family due to its high degree of structural homology. These receptors were renamed OP1, OP2, OP3 and OP4, respectively, by an International Union of Pharmacology (IUPHAR) nomenclature committee in 1996 [1]. This nomenclature has proved unpopular. The nomenclature (X-Opioid Peptide receptor) has been proposed giving mu or MOP; 8, delta or DOP; k, kappa or KOP and ORL1 or NOP receptors. In order to keep matters straightforward the original nomenclature is used in the following chapters.

The products of endogenous opioid peptide genes activate opioid receptors physiologically: proenkephalin (giving methionine- and leucine-enkephalin; Met-enk and Leu-enk, respectively; Figure II-8), prodynorphin (dynorphins A and B and a-neo-endorphin) pro-opiomelanocortin (^-endorphin) and pronociceptin (nociceptin, also known as Orphanin FQ). Met-enk and Leu-enk have highest affinity

Het-Enkepalin

Het-Enkepalin

Morphine Structure
Figure II-8. The tyrosine residue of the endogenous opioid met-enkephalin demonstrates similarity with the molecular structure of morphine and the antagonist naloxone, which is indicative for similar receptor binding sites

for 8-receptors, less affinity for and very low affinity for K-receptors; the dynorphins have preferential affinity for K-receptors, but bind to the ^ and 8 types with high affinity; ^-endorphin binds with high affinity to ^ and 8 receptors, but has little affinity for K receptors. All the peptides are full agonists at their cognate receptors. Endomorphin-1 and -2, derived from an unknown precursor, are endogenous peptides with high selectivity for ^-receptors. These peptides are unusual in that they are partial agonists. None of the proenkephalin, prodynorphin or pro-opiomelanocortin peptide products or the endomorphins displays affinity for the ORL1 receptor.

Similarly, the ORL1 receptor agonist nociceptin has no appreciable affinity for

8 or k receptors.

The four receptor types have been cloned and shown to be 7-transmembrane receptors activating G proteins of the pertussis-toxin insensitive Gai/o family, but including Gaz. Evidence for subtypes of 8 and k opioid receptors exists, but the molecular basis for the observed functional and pharmacological differences is unclear. Putative 81 and 82 receptors are differentiated by several agonist and antagonist ligands. However, there is only one 8 receptor gene, the protein product of which has properties of the putative 82 receptor. The distinction between the proposed ^2 and ^2 receptors is based largely on the apparent preferential blockade of the type by the antagonist, naloxonazine [2]. There is only one cloned ^ receptor gene, corresponding to the putative receptor, but several forms of the ^-receptor mRNA arising from alternative splicing have been reported. The receptors these encode differ at the end of the C-terminal tail and show subtle differences in the binding profile of opioid ligands; a role for the variants is not known.

The cloned K-receptor, with high affinity for U69593 is the k1 subtype. The proposed k2 and k3 subtypes are poorly defined in both molecular and pharmacological terms (Table II-2). A recent explanation for subtypes has evolved with

Table II-2. Summary of the main opioid receptors and the receptor subtypes, their endogenous ligands, their selective exogenous ligands and their functional role

Opioid receptor types and subtypes

Receptor type (Natural ligand)

Selective agonist

Agonist properties

Selective antagonists

| (enkephalins)

morphine

Analgesia Euphoria

Naloxone

((-endorphin)

sufentanil DAGO

Increased

Naltrexone CPT

(Tyr-ala-Gly-MePhe-

gastrointestinal

(d-phe-Cys-Trp-

NH(CH2)2-OH) also

transit time

lys-Thr-NH2)

DAMGO) PLO17 (Tyr-

Tolerance and

Cyprodime

Pro-MePhe-d-Pro-NH2)

physical dependence

(-FNA (affinity

BIT (affinity label)

Immune supression

label)

Respiratory

depression (volume)

Emetic effects

|1 (high affinity)

N-(2-pyrazinyl)-N-

Naloxonazine

(1-phenethyl-4-piperidinyl)-

2-furamide

| 2 (low affinity)

?

N-(2-pyrazinyl)-

N-(1-phenethyl-

4-piperidinyl)-2-

furamides

k (dynorphins)

EKC Bremazocine Mr

Analgesia Sedation

TENA nor-BNI

(( -endorphins)

2034 Dyn (1-17)

Miosis Diuresis

Trifluadom

Dysphoria

K1 (high affinity)

U-50,488 Spiradoline

(U-62,066) U-69,593

PD 117302 UPHIT

(affinity label)

k2

Dyn (1-17)

k3

?

8 (enkephalins)

DADLE (d-Ala2-d-

Analgesia Immune

ICI 174864

(( -endorphin)

Leu5-enkephalin)

stimulation

Naltrindole

DSLET (Tyr-d-Ser-

Respiratory

Gly-Phe-Leu-Thr)

depression

DPDPE (d-Pen2-d-

Pen5-enkephalin) FIT

(affinity label)

SUPERFIT (affinity

label)

Abbreviations nor-BNI: nor-Binaltorphimine BNTX: E-7-Benzylidenenaltrexone

BW373U86:

(±)-(1[S*]2a,5p)-4-(2,5-Dimethyl-4-(2-propenyl)-1-piperazinyl]

[3-hydroxyphenyl]methyl)-N,N-diethylbenzamide

P-CNA:

P-chlornaltrexamine

CRAP:

D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2

CTOP:

D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2

DALCE:

[D-Ala2,Leu5,Cys6]-Enkephalin

DAMGO:

[D-Ala2,N-Me-Phe4,Gly-ol5]-Enkephalin

DPDPE:

[D-Pen2,5]-Enkephalin

DSLET:

[D-Ser2,Leu5,Thr6]-Enkephalin

EKC:

Ethylketocyclazocine

P-FNA:

P-Funaltrexamine

GNTI:

5'-Guanidinylnaltrindole

ICI 174864:

N.N-diallyl-Tyr-Aib-Aib-Phe-Leu

J-113397:

1-[(3R,4R)-1-cycloocylomethyl-3-hydroxymethyl-4-piperdinyl]-3-ethyl-1,

3-dihydro-2H-benzimidazol-2-one

MCAM:

Methocinnomox

5'-NTII:

Naltrindole 5'-isothiocyanate

Ro 64-6198:

(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,2,

8-triaza-spiro[4.5]decan-4 one.

SNC80:

(+)-4-[(«R)-«-((2S5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,

N-diethylbenzamide

(-)-TAN-67:

(-)-2-Methyl-4aa-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aa-octahydroquinolino

[2,3,3-q]isoquinoline

TIPP(^ ):

H-Tyr-Tic^ -[CH2NH]Phe-Phe-OH.

U-69593:

(+)-(5a,7a,8P)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl)

benzeneacetamide

U-50488:

3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide

the identification of opioid receptor heterodimers or hetero-oligomers that appear to have properties different from the monomeric receptors. An interesting addition to ligands that bind to the k1 receptor is the hallucinogen salvinorin-A. This is a highly efficacious and potent k agonist, but is most unusual in that it has no nitrogen atom. Endogenous opioid systems have a functional role in modulating pain perception; opioid agonists are therefore potent analgesics. Opioid receptors are also present in hypothalamus (Figure II-9), where they influence temperature regulation and control of hormonal secretion. In the forebrain, endogenous opioids are involved in behavioral reinforcement and appear to play a role in anxiety and in the expression of emotions. In addition, opioids influence gastrointestinal and autonomic nervous system function.

Originally, a fifth binding site, the sigma receptor, was included in this group. However, actions mediated through this receptor are not reversed by naloxone so it is not a true opioid receptor. The ^-receptors have been further sub-classified into two distinct subtypes (1 and 2), as have the K-receptors. Kappa receptors have been divided into 1, 2, and 3 sub-types. Recently, several of these receptors have been cloned successfully. In animal models, some laboratories have cloned up to 10 ^-receptor subtypes [4]. However, the functional significance of these "spliced variants" remains unclear at present. Originally suggested by Martin and coworkers [5], all three opioid receptor types mediate different opiate effects as they

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