synthesis and in vitro pharmacology of a series of histamine h2 ...

Chapter 8
Dimaprit 3 (fig. 1) is an agonist for the histamine H2-receptor 7
(pD2 = 5.7 on the
guinea pig right atrium), while it is an antagonist for the histamine H3-receptor 6
(pA2 = 5.5; histamine release rat cortex). Structure-activity relationship studies on dimaprit,
S-[3-(N,N-dimethylamino)propyl]isothiourea, revealed that the dimethylamino group
has the same function as the amino group of histamine, while the isothiourea group of
dimaprit and the imidazole group are regarded bioisosteric for the histamine H2 agonist 8
.
Two models have been proposed for the mechanism of action of the monocation of
dimaprit, which is the active species. The first model (the so-called N-fit) implies that
the amidino group of dimaprit participates in tautomerism or bifunctional acceptordonor
hydrogen bonding 8
, analogous to the activation mechanism described for
histamine at the H2-receptor 9
. The second model (the so-called S-fit) suggests that the
acceptor-donor hydrogen bonding of dimaprit is provided by the sulfur atom and by
a proton of the amidino group 10
. Quantum chemical calculations have suggested that
1 !
the S-fit conformation is the most favourable for interaction with the Hrreceptor » 12
.
Furthermore, similar calculations on 2-amino-5-(2-aminoethyl)thiazole 13
6 (fig. 2)
revealed that this compound can be considered as a ring-closed dimaprit
analogue 14
* 15
. Indeed, several substituted 2-aminothiazole derivatives have been
shown to be active at the histamine H2-receptor, of which amthamine 16
7 (fig. 2) is
the most potent H2-agonist in this series (pD2 = 6.30; guinea pig right atrium).
H 2N
Figure 2: Substituted 2-amino-5-(2-aminoethyl)thiazole derivatives
There are several compounds which show that tautomerism is not involved in
stimulation of the histamine H2-receptor. Eriks et al. 17
have developed a new
activation model for the histamine H2-receptor, which explains the activities of all
known tautomeric and nontautomeric H2-agonists. In their model, protonation of the
double-bonded nitrogen atom of heterocyclic rings induces a positive charge, which
is distributed over the ring. The distribution of the positive charge enables an ionic
interaction of the heterocyclic ring with a negatively charged receptor site. For the
mechanism of action of thiazoles, which cannot undergo tautomerism because of the
inability to protonate the partially positively charged sulfur atom, an other
explanation has been proposed 17
.
In impromidine, the 3-[4(5)-imidazolyl]propylguanidine moiety is important for
triggering the histamine H 2-receptor. Replacement of the 3-[4(5)-imidazolyl]propyl
192