Improgan-like Analgesics: A Family of Compounds Derived From Histamine Anatgonists

The a ntinociceptive activity of some c entrally-administered H 2 antagonists has led to the development of improgan-like analgesics, which produce powerful suppression of pain responses when injected into the brain. Although selected H 2 and H 3 antagonists have antinociceptive activity, structure-activity studies and other results have shown that blockade of neither receptor accounts for the pain-relieving properties of these drugs. Although improgan does not act through known histamine or opioid receptors, and over 60 receptors and ion channels have been excluded as targets for improgan action, the mechanism of action of improgan remains unknown. In vivo studies have shown that improgan activates non-opioid, descending, pain-relieving circuits in both the periaqueductal gray and raphe magnus. These circuits use brain stem CB 1 receptors and spinal alpha2 adrenergic receptors, but improgan does not act directly at these receptor sites. New findings show that a variety of aromatic heterocyclic derivatives in this series can produce potent antinociception. However, all such compounds in this series may not be acting by identical mechanisms. Development of more potent, brain-penetrating derivatives may lead to the discovery of effective non-opioid analgesics.