- H 2 receptors are localized to the cortex and striatum and are found in neurons, glial
cells (astrocytes), and blood vessels. They are coupled to AC; their stimulation has
a central disinhibitory effect, due to the decrease in Ca^2 +-activated K+conductance.
Thus the role of the central histamine receptor may not be information transmission,
but sensitization of brain areas to excitatory signals from “waking amines.” - H 3 receptors have been described and seem to be localized in cortex and substantia
nigra; these seem to be presynaptic autoreceptors, controlling histamine release and
synthesis. They are activated by histamine concentrations that are two orders of
magnitude lower than those necessary for triggering postsynaptic receptors. Their
blockade may potentially lead to increased blood flow and metabolism combined
with a central arousal, whereas their stimulation (or inhibition of central H 2 receptors)
could have a sedative effect.
Knowledge of the physiological role of histamine in the CNS and evidence for the
existence of discrete neuronal networks that could be called histaminergic are still evolv-
ing. Histamine-mediated hypothermia, emesis, and hypertension have been shown to
exist, and the well-known sedative effects of H 1 antihistamines are centrally mediated.
4.6.3 Histamine AgonistsA selection of agonists is shown. 4-Methylhistamine (4.140) is selective for the H 2
receptor, whereas the 2-methyl derivative (4.141) is a weak but usable H 1 agonist. The
fact that the 2-pyridyl (4.142) and 2-thiazolyl rings (4.143) also lend H 1 activity to
histamine derivatives shows that tautomerism is not an issue in H 1 activity. Large alkyl
groups on C-4 decrease activity and lead to partial agonists, whereas side-chain
N-substitution enhances the antagonistic properties of the molecule.
An interesting histamine agonist is dimaprit (4.144), which was described in the late
1970s. It is a selective H 2 agonist, having between 19% and 70% H 2 activity, with no
effect on the H 1 receptor. The isothiourea system in dimaprit has a planar electron
sextet, like that of the imidazole ring in histamine, and is capable of tautomerism as
264 MEDICINAL CHEMISTRY