Antihistamines (Medicinal chemistry) Manik

Antihistamines (Medicinal chemistry) Manik

• 2.
  Katzung, Bertram G.,Susan B. Masters, and Anthony J. Trevor. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill Medical, 2012. Goodman, Louis S, Alfred Gilman, and Laurence L Brunton. Goodman & Gilman's Manual of Pharmacology and Therapeutics. New York: McGraw-Hill Medical, 2008. Remington, Joseph P. Remington, the Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co., 1995. Richard Finkel, Michelle A. Clark, Luigi X. Lippincott's Illustrated Reviews: Pharmacology. 6th ed. Baltimore, MD; New Delhi: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2012. H P Rang, M M Dale, J M Ritter, R J Flower, G Henderson RANG AND DALE’S Pharmacology. 7th ed. Elsevier Inc. 2007. Ashutosh Kar. Medicinal Chemistry. 4th ed. New Delhi: New Age International, 2007.
• 3.
  Histamine is synthesizedin cytoplasmic granules of its principal storage cells (mast cells & basophil) from naturally occurring amino acid S-histidine via catalysis of pyridoxal phosphate dependant histidine decarboxylase.
• 4.
  Allergies and anaphylaxiscan also trigger significant release of histamine, where histamine release is initiated by the interaction of an antigen-antibody (IgE) complex with the membrane of a histamine storage cell. Exocytotic release of histamine follows the degranulation of the storage cell. Histamine is released from mast cells in the gastric mucosa by gastrin & acetylcholine. Most histamine is synthesized & stored in mast cells & basophils. Histamine is also stored in selected neuronal tracts in the CNS. Protein-complexed histamine is stored in secretory granules & released by exocytosis in response to a wide variety of immune & non-immune stimuli. The stimuli for release of histamine from tissues may include destruction of cells as a result of cold, toxins from organisms, venoms from insects and spiders, and trauma.
• 5.
  Four different histaminereceptors have been characterized and are designated H1 –H4 all of which are G protein-coupled receptors. These different receptors are expressed on different cell types and work through different intracellular signalling mechanisms, which explain, at least at a simple level, the diverse effects of histamine in different cells and tissues. Receptor Type Major Tissue Locations Major Biologic Effects H1 Smooth muscle, Endothelial cells and Nerve endings. Acute allergic responses, vasodilatation, Contraction of most smooth muscle, except blood vessels. H2 Gastric parietal cells (gastric mucosa), Cardiac muscle cells, Mast cells and Brain. Stimulation of gastric secretion. H3 Central nervous system (Presynaptic autoreceptors and heteroreceptors) Modulating neurotransmission H4 Intestinal tissue, Spleen, Thymus & Immune active cells such as- T cells, Neutrophils, Eosinophils. Regulating immune responses
• 6.
  The term antihistaminehistorically has referred to drugs that antagonize the actions of histamine at H1-receptors. The H1-antagonists are now commonly subdivided into two broad groups - the first generation or classical antihistamines and the second generation or “non-sedating” antihistamines – based primarily on their general pharmacological profiles. The first generation or classical antihistamines are related structurally and include a number of aminoalkyl ethers, ethylenediamines, piperazines, propylamines, phenothiazines and dibenzocycloheptenes. In addition to H1-receptor antagonism, these compounds display an array of other pharmacological activities which contribute toward therapeutic applications and adverse reactions. More recently, a number of second generation or “non-sedating” antihistamines have been developed and introduced. The second generation agents bear some structural resemblance to the first generation agents, but have been modified to be more specific in action and limited in their distribution profiles.
• 7.
  (i) Aminoalkylethers :Examples-Diphenhydramine Hydrochloride ; Bromodiphenhydramine Hydrochloride ; Dimenhydrinate ; Doxylamine Succinate ; Diphenylpyraline Hydrochloride. (ii) Ethylenediamines : Examples-Mepyramine Maleate ; Tripelennamine Hydrochloride, Thonzylamine Hydrochloride ; Zolamine Hydrochloride. (iii) Thiophene Derivatives: Examples-Methapyrilene Hydrochloride; Methaphenilene Hydrochloride, Thenyldiamine Hydrochloride; Chlorothen Citrate. (iv) Alkylamine derivative: Chlorpheniramine Maleate
• 8.
  (v) Cyclic BasicChain Analogues: Examples- (a) Imidazoline Derivatives, e.g., Antazoline Hydrochloride (b) Piperazine Derivatives, e.g., Cyclizine Hydrochloride ; Chlorcyclizine Hydrochloride ; Meclizine Hydrochloride ; Buclizine Hydrochloride ; (c) Piperidine Derivativs, e.g., Thenalidine Tartrate. (vi) Phenothiazine Derivatives: Examples-Promethazine Hydrochoride ; Promethazine Teoclate ; Trimeprazine Tartrate ; Methdilazine Hydrochloride. (vii) Second-generation Non-Sedating Antihistamines: Examples: Terfenadine ; Astemizole ; Loratadine ; Acrivastine ;Fexofenadine (viii) Miscellaneous Agents: Examples-Phenindamine Tartrate; Triprolidine Hydrochloride; Cyproheptadine Hydrochloride.
• 9.
  The diaryl substitutionpattern is present in both the first and second generation antihistamines and is essential for significant H1-receptor affinity. Most H1-antagonists contain substituents in one of the aryl rings (usually benzene), and these influence antihistamine potency, as well as bio disposition. In many of the first generation antihistamines the terminal nitrogen atom is a simple dimethyl amino moiety. However, the amine may also be part of a heterocyclic structure, as illustrated by the piperazine, some propylamines (pyrrolidines and piperdines), some phenothiazines, the dibenzocycloheptenes and the second generation antihistamines. In all cases the amino moiety is basic with pKas ranging from 8.5 to 10 and thus presumed to be protonated when bound on the receptor. X is a connecting atom of O, C or N. The X connecting moiety of typical H1-antagonists may be a saturated carbon-oxygen moiety or simply a carbon or nitrogen atom. This group along with the carbon chain appears to serve primarily as a spacer group for the key pharmacophoric moieties.
• 10.
  Many of theanthistamines containing a carbon atom in the connecting moiety are chiral, and exhibit stereoselective receptor binding. For example, in the pheniramine series and carbinoxamine, this atom is chiral and in vitro analysis indicates that those enantiomers with the S-configuration have higher H1-receptor affinity. The (CH2)n group and connecting atom results in a distance between the central point of the diaryl ring system and the terminal nitrogen atom in the extended conformation of the antihistamines ranging from 5 to 6 angstroms (a "spacer" group). In some series branching of the carbon chain results in a reduction of antihistaminic activity. However, there are exceptions as evidence by promethazine which has a greater activity than its non-branched counterpart. When the carbon adjacent to the terminal nitrogen atom is branched, the possibility of asymmetry exists. However, stereoselective H1-receptor antagonism typically is not observed when chirality exists at this site. Also, in those compounds which possess an asymmetrically substituted unsaturated carbon chain (pyrrobutamine and triprolidine) one geometric isomer typically displays higher receptor affinity than the other.
• 11.
  Generally, the firstand second generation anthistamines are substantially more lipophilic than the endogenous agonist histamine (or the H2-antagonists). This lipophilicity difference results primarily from the presence of the two aryl rings, and the substituted amino moieties, and thus may simply reflect the different structural requirements for antagonist versus agonist action at H1-receptors. Features First generation H1 receptor blocker Second generation H1 receptor blocker Daily Doses Usually three to four daily doses Usually once or twice a day Blood-brain barrier Cross the BBB Don’t cross the BBB Side effects Potentially occurs Do not cause relevant side effects Common side effects sedation/hyperactivity/insomnia/ convulsions sedation/fatigue/hyperactivity/ convulsions Toxicity Case reports regularly published No reports of serious toxicity Lethal dose Lethal dose identified for infants/young children Do not cause fatality in overdose
• 12.
  Gastric acid issecreted from parietal cells located mainly in the upper portion of the stomach and is stimulated by three endogenous substances: gastrin, acetylch oline, and histamine. The parietal cell contains receptors for gastrin, acetylcholine (muscarinic, M3), and histamine (H2). When acetylcholine or gastrin binds to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from an H+/K+ ATPase (the proton pump) on the canalicular surface
• 13.
  In close proximityto the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin and acetylcholine. It is thought that gastrin and acetylcholine act on ECL cells to release histamine. Histamine then binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP), cAMP activates protein kinases that stimulate acid secretion by the H+/K+ ATPase. Figure: Schematic diagram of one model of the physiologic control of hydrogen Ion secretion by the gastric parietal cell. EC cell, enterochromaffin- like cell; G(CCK-B>, gastrih-chdlecystokinin-B receptor; H, histamine; H2. histamine Ha receptor; M1, M3, muscarinic receptors; ST2 somatostatin receptor; ATPase,Kf/Ht ATPase proton pump. Some investigators place histamine receptors—and possibly cholinoceptors—on nearby tissue cells rather than on the parietal cell Itself. (Modified and redrawn from Sachs 6,Prinz C:Gast ric enterochromaffin-like cells and the regulation of acid secret.on.News Physiol Set 1996eU:S7,and ot her sources)
• 14.
  The H2 receptorantagonists in clinical use are histamine congeners that contain a bulky side chain in place of the ethylamine moiety. Early representatives of the group, such as burimamide and cimetidine (the first compound released for general use) retain the imidazole ring of histamine. This ring is replaced in more recently developed compounds by a furan (ranitidine) or a thiazole (famotidine, nizatidine). HN N CH2CH2NH2 Histamine HN N H2 CH3C S H2 C C H2 H N C NH CH3 N C N Cimetidine O H2CN H3C H3C H2 C S H2 C C H2 H N C H N CH3 CH NO2 Ranitidine N S N H2 C S H2 C C H2 Famotidine C H2N H2N C N SO2NH2 NH2
• 15.
  The H2 receptorantagonists exhibit competitive inhibition at the parietal cell H2 receptor, and suppress basal (fasting), nocturnal and meal stimulated acid secretion in a linear dose-dependent manner. They are highly selective and do not affect H1 or H3 receptors H2 antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms: First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2 receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine results in diminished acid secretion in the presence of H2 receptor blockade. It appears that reduced parietal cell cAMP levels attenuate the intracellular activation of protein kinases by gastrin or acetylcholine.