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

388
β-LPH
Signal peptide
JP ACTH γ-LPH
pre-POMC
γ-MSH
α-MSH CLIP 1 β-MSH β-end
Signal peptidase
JP ACTH β-LPH
SECTION II
PC1
JP ACTH β-LPH
PC1
NEUROPHARMACOLOGY
PC2
JP
PC1
JP
ACTH
PC2
PC1
γ-MSH α-MSH CLIP γ-LPH β-end
Figure 14–16. Proteolytic processing of praopiomelanocortin (POMC). After removal of the signal peptide from pre- POMC, the remaining
propeptide undergoes endoprotolysis by prohormone convertases 1 and 2 (PC1 and PC2) at dibasic residues. PC1 liberates the
bioactive peptides adrenocorticotropic hormone (ACTH), β- endorphin (β end), and γ- lipotrophic hormone (γ- LPH). PC2 cleaves
ACTH into corticotrophin- like intermediate lobe peptide (CLIP) and α-melanocyte stimulating hormone (α-MSH) and also releases
γ- MSH from the N- terminal portion of the propeptide. The joining peptide (JP) is the region between ACTH and γ-MSH. β-MSH is
formed by cleavage of γ-LPH. Some of the resulting peptides are amidated or acetylated before they become fully active.
β-MSH
molecules capable of acting at peptide receptors might have been
deemed impossible to develop.
Other Regulatory Substances
Cannnabinoids. Delta-9-tetrahydrocannabinol (THC) is one of several
active substances in marijuana (Figure 14–17). It has dramatic
short- term effects, including causing feelings of euphoria and altered
sensory perception. After chronic or long- term use, withdrawal
symptoms include irritability and sleep disturbances. The primary
pharmacologic effects of THC follow its interaction with CB 1
receptors
in the CNS and CB 2
receptors in the periphery. CB 1
receptors are
found primarily in the basal ganglia, hippocampus, cerebellum, and
cerebral cortex. They are also expressed in some non- neuronal cells
and tissues, including leukocytes and testis. CB 2
receptors are
expressed in the spleen, tonsils, bone marrow, and on peripheral
blood leukocytes. The natural endogenous ligands for these receptors
are arachidonic acid derivatives including anandamide and 2-
arachidonyl glycerol (Figure 14–17). Both CB 1
and CB 2
receptors
are linked to G i
and inhibition of adenylyl cyclase activity. Activation
of CB 1
receptors results in inhibition of glutamate release. Efforts
to develop CB 1
antagonists like rimonabant have focused on possible
treatments for drug addiction and obesity. Efforts are also underway
to develop agonists that interact with CB 1
and CB 2
receptors
for the relief of pain. THC (dronabinol, MARINOL) is sometimes used
in the control of nausea and moderate pain (Chapter 46).
Purines. Adenosine, ATP, UDP, and UTP have roles as extracellular
signaling molecules (Robertson et al., 2001; Siegel et al., 2006).
High concentrations of ATP are found in adrenergic storage vesicles
and ATP is released along with catecholamines and the other contents