DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 18–1
Actions and Selectivities of Some Opioids at μ, δ, and κ Receptors (Continued)
RECEPTOR TYPES
OPIOID LIGANDS μ δ κ
Antagonists
Naloxone d − − − − − −
Naltrexone d − − − − − − −
CTOP a
Diprenorphine − − − − − − − −
β-Funaltrexamine a,e − − − − ++
Naloxonazine − − − − −
nor-Binaltorphimine − − − − −
Naltrindole b − − − − −
Naloxone benzoylhydrazone − − − – –
a
Protoypical μ-preferring. b Prototypical δ- preferring. c Prototypical κ- preferring. d Universal ligand. e Irreversible ligand. +, agonist; –, antagonist;
P, partial agonist. The number of symbols is an indication of potency; the ratio for a given drug denotes selectivity. These values are obtained primarily
from a composite overview of results obtained in vivo/in vitro animal pharmacological work and in ligand binding and activity studies and
should be extrapolated to humans with caution.
Source: Reproduced with permission from Raynor et al, 1994.
− − −
extensive sequence homologies (55-58%). The greatest
diversity is found in their extracellular loops. In
addition, all opioid receptors possess two conserved
cysteine residues in the first and second extracellular
loops forming a disulfide bridge.
μ, δ, and κ opioid receptors are widely distributed
and this distribution has been examined in detail
using immunohistochemistry, in situ hybridization,
and more recently by noninvasive imaging techniques.
The profound and diverse effects on CNS function are
consistent with the density and diverse distribution of
receptors in the brain and spinal cord (Henriksen et
al., 2008). In addition, these receptors are expressed in
a wide variety of peripheral tissues, including vascular,
cardiac, airway/lung, gut, and many resident and
circulating immune/inflammatory cells (discussed
subsequently).
Following the cloning of the classical opioid receptors, the G-
protein coupled opiate receptor-like protein (ORL1 or NOP) was
cloned based on its structural homology (48-49% identity) to other
members of the opioid receptor family; it has an endogenous ligand,
nociceptin/orphanin (FQ: N/OFQ) (Stevens, 2009). See Figure 18–2.
Since this system does not display an opioid pharmacology (Fioravanti
et al., 2008), it will not be discussed in detail in this chapter.
N/OFQ binding sites have been found to be largely in the
CNS and to be densely distributed in cortical regions, ventral forebrain,
hippocampus, brainstem, and spinal cord, as well as in a number
of peripheral cells including basophils, endothelial cells, and
macrophages.
Opiate Receptor Subtypes
The existence of three classes of opiate receptors (MOR, DOR, and
KOR) is widely accepted. The opioid receptors appear early in vertebrate
evolution, being already present with the appearance of jawed
vertebrates. The human opiate receptors have been mapped to chromosome
1p355-33 (DOR), chromosome 8q11.23-21 (KOR), chromosome
6q25-26 (MOR), and chromosome 20q13.33 (NOR)
(Dreborg et al., 2008). Low-stringency hybridization procedures
have identified no opioid receptor types other than the cloned opioid
receptors. Nevertheless, pharmacological studies have suggested the
possible existence of at least two subtypes of each receptor. While
cloning studies have not supported the existence of these subtypes as
distinct classes, the modified specificity for opioid ligands may result
from several underlying events.
Heterodimerization. In the membrane, opiate receptors can form
both homo- and heterodimers. Dimerization can alter the pharmacological
properties of the respective receptors. For example, DORs
form heterodimers with both MORs and KORs. Thus, MOR-DOR
and DOR-KOR heterodimers show less affinity for highly selective
agonists, reduced agonist-induced receptor trafficking, and mutual
synergy between receptor-selective agonists in binding to the