Biomedical Engineering Reference
In-Depth Information
Impentamine
NH 2
H-N
N
1400
H
1200
Cl
1000
H
800
600
CH 3
H
CH 3
400
CH 3
200
N
CH 3
0
-12
-11
-10
-9 -8 -7
Log [Compound, M]
-6
-5
-4
FIGURE 17.6 Alkylation of the primary amine function of impentamine leads to ligands that cover the
complete spectrum of functional activity, i.e., agonism, neutral antagonism, and inverse agonism.
(the compound is able to penetrate the CNS). However, thioperamide displays some 5-HT 3
receptor antagonism and also is an inverse agonist at the H 4 receptor. Moreover, a remarkable H 3
receptor species differences can be demonstrated with thioperamide, as the compound has a 10-fold
higher afi nity for the rat H 3 receptor than for the human H 3 receptor. Based on the H 3 receptor ago-
nist imetit, the highly potent H 3 inverse agonist clobenpropit was developed (pA 2 = 9.9). This com-
pound also has some 5-HT 3 receptor activity and displays partial agonist activity at H 4 receptors.
Impentamine is a potent histamine H 3 receptor partial agonist in SK-N-MC cells expressing human
H 3 receptors. It has also been shown that small structural modii cations of impentamine, i.e., alkyla-
tion of the primary amine moiety of impentamine with, e.g., methyl-, isopropyl-, and p -chlorobenzyl-
groups results in ligands that cover the complete spectrum of functional activity, i.e., agonism,
neutral antagonism, and inverse agonism (Figure 17.6). The compound VUF5681 (Figure 17.5) was
reported as a neutral H 3 antagonist, not affecting the basal signaling of the histamine H 3 receptor.
As such, it has proven to be a useful molecular tool in H 3 receptor studies, for example, when studying
H 3 constitutive activity in the rat brain.
The imidazole-containing compounds have been very important in characterizing the H 3 receptor.
Furthermore, similarity studies resulted in pharmacophore models (Figure 17.7) that explain the SAR
of the different classes of imidazole-containing ligands and indirectly describe the ligand-binding
site of the receptor.
Imidazole-containing ligands are associated with inhibition of cytochrome P-450 enzymes. Via
this mechanism, the clearance of coadministrated drugs can be compromised, leading to severe
drug-drug interactions and extrapyramidal symptoms. Classic medicinal chemistry work, ele-
gantly conducted by the team of Ganellin (already involved in the development of the H 2 antagonist
cimetidine, vide supra ) at University College London led to a i rst breakthrough in the search of
nonimidazole H 3 antagonists, as illustrated in Scheme 17.3. The endogenous agonist histamine was
once again taken as a lead structure. Attachment of a lipophilic group to the amine moiety led to
 
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