Biomedical Engineering Reference
In-Depth Information
HO
H
OH
n
O
O
+
O
N
N
N
H
H
N
O
+
O
O
n
H
OH
OH
19.1
HO
H
OH
+
N
N
O
N
N
N
O
O
O
N
+
n
O
O
NH
HO
H
O
OH
O
19.2
FIGURE 19.6
Examples of dimeric or bivalent opioid receptor ligands.
HO
HO
HO
O
O
N
O
N
N
N
OH
H
2
N
H
NH
2
N
H
2
N
NH
2
N
H
2
N
H
O
O
OH
OH
O
NH
2
H
HO
S
Endomorphin-2
19.3
O
19.4
FIGURE 19.7
Examples of peptidomimetic opioid receptor ligands.
Today there is a substantial evidence to show that G-protein coupled receptors exist as dim-
ers. The concept of making bivalent ligands has been shown to be applicable in many other areas
wherein it is possible to modulate other pharmacological properties of a ligand such as degrada-
tion, uptake, etc. The concept has also been used to target heterodimeric receptor populations. For
example, the dimerization of the analogues of naltrexone and NTI yields a series of heterobivalent
ligands
19.2
(
n
= 2-7), where tolerance and dependence are signii cantly reduced with increasing
linker length, whereas agonist potency is increased. It is hypothesized that d-k heterodimers are tar-
geted specii cally with longer linkers. Also, ligands that selectively target d-k heterodimers, which
are localized in the spinal cord, have been developed.
The last approach that will be mentioned here is the use of peptides and peptidomimetics. New
agonists and antagonists of opioid receptors have been obtained by making large combinatorial
libraries of d- and l-amino acids including mix libraries and screening these compounds against
MOR, KOR, and DOR. The sequences span from tetra- to decapeptides. In this way, potent and
selective peptides have been obtained that differ from the endogenous peptides. Furthermore,
the modii cation of the peptide backbone has yielded potent peptidomimetics. The modii cations
include minor modii cations such as backbone amide alkylation. But examples of more extensive
modii cations are the use of a polyamine backbone as in compound
19.3
, or compound
19.4
, which
is a peptidomimetic analogue of endomorphin-2, a potent agonist of MOR with high selectivity for
MOR over DOR and KOR (Figure 19.7).
19.1.4 T
HERAPEUTIC
A
PPLICATIONS
AND
P
ROSPECTS
Although the development of opiates has been spurred primarily by the search for efi cient anal-
gesics wit h few side effects, ot her clin ica l applications of opioid receptor agon ists a nd a ntagon ists
