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

Chapter 1
0C2-ADRENOCEPTOR ANTAGONISTS active at peripheral arterial (^-adrenoceptors
The selective a 2-adrenoceptor antagonists SK&F 86466 49 and SK&F 104078 50
(fig. 9d) have been shown to reduce blood pressure in some animal models, by
blocking the post-synaptic a2-adrenoceptor 63
. However, in humans SK&F 86466
caused tachycardia and had little effect on blood pressure. Post-synaptic a 2-
adrenoceptor blockers are important tools in identifying the vascular oc 2-
adrenoceptor. However, in contrast to vascular a radrenergic antagonists, post­
synaptic vascular a 2-adrenoceptor antagonists have not yet been established in
antihypertensive treatment.
R
49 SK&F 86466 R = H
50 SK&F 104078 R = OCH 2CH=C(CH 3) 2
Figure 9d: Antihypertensives; o^-adrenoceptor antagonist
3.4.6 Potassium channel activators
K +
-channel activators affect K +
-channels in cardiac muscles, neurones, and in
secretory cells but exhibit their greatest effect in the smooth muscle system 64
. Since
cromakalim 51 (fig. 9e) was discovered to enhance the transport of potassium ions
across smooth muscle membranes, it increased the interest in the function of ATPsensitive
K +
6 5 6 6
-channels ' . K+-channel activators are under development for
treatment of hypertension, angina and asthma. K +
-channel activators relax vascular
smooth muscle and protect the heart during acute ischemia 67
. Different tissues, like
smooth muscle, pancreatic and cardiac cells have different subtypes of ATP-sensitive
K +
-channels 68
. Various activators of the ATP-sensitive K +
-channels in cardiac cells
(like nicorandil 52, pinacidil 53; fig. 9e) protect the myocardium without depressing
myocardial function. Nicorandil has additional properties such as vasodilation
because of the present nitrate ester (see antianginal drugs).
Recently, aprikalim 54 (fig. 9e) was selected for further investigations to establish the
antihypertensive and antianginal actions 69
. Attempts have been made by Brown et
al. 70
to remove one of the chiral centers of aprikalim to give synthetically easily
accessible compounds, but this has led to less active compounds.
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