University:
Kentucky State University
Course:
CHE 315 | Biochemistry
Academic year:

2024
Views:

310

Pages:

28
Author:

Hundebuchesn

Medicinal Chemistry - II Antihistamines, Antiallergic and Antiulcer Agents Histamine Synthesized in the Golgi apparatus of mast cells and basophils by enzymatic decarboxylation of histidine Also synthesized in the gastrie mucosa, and neurons of the central nervous system (CNS) and in the periphery • Effects include: massive bronchial spasm and effects on smooth muscle and the vasculature, anaphylactic shock. Histamine receptors H, H₂ and H, and most recently H G protein-coupled receptors • H, receptors: Allergic inflammatory responses Contraction of smooth muscles in gut, uterus and bronchi Smooth musele relaxation in fine blood vessels resulting in vasodilation, may result in severe hypotension •H₂ receptors Regulation of gastric acid secretion Histamine CNS, H, and H, receptors, predominantly localized on postsynaptic membranes: -Physiologic role at axons in several regions of the CNS Role in the regulation of sleeping and waking, in energy and endocrine homeostasis and in cognition and memory •H₂ receptors: Modulates the release of neurotransmitters Function predominantly as presynaptic receptors Detected in some peripheral organs • H, receptor: Very restricted locations in intestinal tissue, spleen and immune active cells, e.g., mast cells, eosinophils and T-cells Proinflammatory mediators First Generation Histamine H₁-Antagonists Ethanolamine Ethers, Cont Chiral center due to differences in the two aromatic rings Levo (S) isomers are more potent than the dextro (R): Levo (S) carbinoxamine is 24 times more potent than the dextro (R) Implies that the receptor must possess a degree of asymmetry in the area of rings hinding Carhinoxamine Clemastine, with two chiral centers, potency order is: R.RR.SS.RS.S The configuration of the chiral center at the benzhydryl carbon (close to the rings) has a more significant influence on potency than the centre close to the nitrogen (pyrrolidine ring) Clemastine First Generation Histamine H₁-Antagonists Ethanolamine Ethers, Cont Retro arrangement of carbon and oxygen atoms led to a series of very important selective serotonin reuptake inhibitors Conversion of the oxygen atom to a sulfur atom results in a great decrease in antihistaminic activity Phenyltoloxamine Diphenhydramine (Weak anthistamine (serotonin reuptake inhibito Structural similarities among diphenhydramine related structures