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

220 M 1
through M 5
muscarinic receptors (Chapter 8). All of
the known muscarinic receptors are G protein-coupled
receptors that in turn couple to various cellular effectors
(Chapter 3). Although selectivity is not absolute, stimulation
of M 1
, M 3
, and M 5
receptors causes hydrolysis of
polyphosphoinositides and mobilization of intracellular
Ca 2+ as a consequence of activation of the G q
-PLC pathway
(Chapter 8), resulting in a variety of Ca 2+ -mediated
responses. In contrast, M 2
and M 4
muscarinic receptors
inhibit adenylyl cyclase and regulate specific ion channels
via their coupling to the pertussis toxin–sensitive
G proteins, G i
and G o
(Chapter 3).
SECTION II
NEUROPHARMACOLOGY
The binding site for the endogenous agonist ACh, the
orthosteric site (Neubig et al., 2003), is highly conserved among
muscarinic receptor subtypes (Hulme et al., 2003). By analogy with
the position of retinal in the orthosteric site of the mammalian
rhodopsin receptor structure (Palczewski et al., 2000), the ACh
orthosteric binding site is putatively located toward the extracellular
regions of a cleft formed by several of the receptor’s seven transmembrane
helices. An aspartic acid present in the N-terminal portion
of the third transmembrane helix of all five muscarinic receptor subtypes
is believed to form an ionic bond with the cationic quaternary
nitrogen in ACh and the tertiary or quaternary nitrogen of antagonists
(Caulfield and Birdsall, 1998; Wess, 1996).
The five muscarinic receptor subtypes are widely distributed
in both the CNS and peripheral tissues; most cells express at least
two subtypes (Abrams et al., 2006; Wess, 1996; Wess et al., 2007).
Identifying the role of a specific subtype in mediating a particular
muscarinic response to ACh has been difficult due to the lack of subtype-specific
agonists and antagonists. More recently, gene-targeting
techniques have been used to elucidate the functions of each subtype
(Wess et al., 2007). These techniques have allowed the creation
of mutant mice with null alleles for the genes of each of the muscarinic
receptor subtypes (Gomeza et al., 1999; Hamilton et al.,
1997; Matsui et al., 2000; Wess, 2004; Yamada et al., 2001a, 2001b).
All of these muscarinic receptor knockout mice are viable and fertile.
The minimal phenotypic alteration that accompanies deletion
of a single receptor subtype suggests functional redundancy between
receptor subtypes in various tissues. For example, abolition of
cholinergic bronchoconstriction, salivation, pupillary constriction,
and bladder contraction generally requires deletion of more than a
single receptor subtype. Such knockout mice studies have resulted
in an increased understanding of the physiological roles of the individual
muscarinic receptor subtypes (Wess et al., 2007; Table 8–3);
many of the findings are consistent with the results obtained from
examining the localization of muscarinic receptor subtypes in human
tissues (Abrams et al., 2006). Although there is functional redundancy,
the M 2
receptor is the predominant subtype in the cholinergic
control of the heart, while the M 3
receptor is the predominant subtype
in the cholinergic control of smooth muscle, secretory glands,
and the eye. The M 1
receptor has an important role in the modulation
of nicotinic cholinergic transmission in ganglia.
Although antagonists that can discriminate between various
muscarinic receptor subtypes have been identified, the development
of selective agonists and antagonists has generally been difficult
because of the high conservation of the orthosteric site across
subtypes (Conn et al., 2009b). Muscarinic receptors seem to possess
topographically distinct allosteric binding sites, with at least one
being located in the extracellular loops and outermost segments of
different transmembrane helices; these sites are less conserved across
receptor subtypes than the orthosteric binding site and thus offer the
potential for greater subtype-selective targeting (Birdsall and
Lazareno, 2005; May et al., 2007). Ligands that bind to allosteric
sites are called allosteric modulators, because they can change the
conformation of the receptor to modulate the affinity or efficacy of
the orthosteric ligand. Progress has been made in developing selective
positive allosteric modulators (PAMs) as important candidates
for drugs with muscarinic receptor subtype selectivity, especially in
the CNS (Conn et al., 2009a, 2009b). Selective negative allosteric
modulators (NAMs), which act at an allosteric site to reduce the
responsiveness of specific muscarinic receptor subtype(s) to ACh,
also may become important therapeutic agents in the future. In both
instances, the modulators do not activate the receptor by themselves,
but can potentiate (in the case of PAMs) or inhibit (in the case of
NAMs) receptor activation by ACh at specific muscarinic receptor
subtype(s). Allosteric agonists have also been identified that appear
to mediate receptor activation through a distinct allosteric site even
in the absence of an orthosteric agonist (Nawaratne et al., 2008).
Another potential mechanism for achieving selectivity is though the
development of hybrid, bitopic orthosteric/allosteric ligands, which
interact with both the orthosteric site and an allosteric site, a mechanism
recently demonstrated to explain the unique effects of the M 1
selective agonist McN-A-343 (Valant et al., 2008).
Pharmacological Effects of Acetylcholine
The influence of ACh and parasympathetic innervation
on various organs and tissues was introduced in
Chapter 8; a more detailed description of the effects of
ACh is presented here as background for understanding
the physiological basis for the therapeutic uses of
the muscarinic receptor agonists and antagonists.
Cardiovascular System. ACh has four primary effects
on the cardiovascular system:
• vasodilation
• decrease in heart rate (negative chronotropic
effect)
• decrease in the conduction velocity in the atrioventricular
(AV) node (negative dromotropic effect)
• decrease in the force of cardiac contraction (negative
inotropic effect)
The last effect is of lesser significance in the ventricles
than in the atria. Some of the above responses
can be obscured by baroreceptor and other reflexes that
dampen the direct responses to ACh.
Although ACh rarely is given systemically, its cardiac
actions are important because the cardiac effects of
cardiac glycosides, anti-arrhythmic agents, and many other
drugs are at least partly due to changes in parasympathetic
(vagal) stimulation of the heart; in addition, afferent