MEDICINAL-CHEMISTRY-OF-ANTIHISTAMINIC-AGENTS_BP501TT.pdf

ANTIHISTAMINIC AGENTS Dr. Navneet F. Chauhan, Ph.D Associate Professor Saraswati Institute of Pharmaceutical Sciences, Gandhinagar  HISTAMINE CHEMISTRY Histamine, 4-(2-aminoethyl) imidazole is composed of an imidazole heterocycle and ethylamine side chain....

ANTIHISTAMINIC AGENTS Dr. Navneet F. Chauhan, Ph.D Associate Professor Saraswati Institute of Pharmaceutical Sciences, Gandhinagar  HISTAMINE CHEMISTRY Histamine, 4-(2-aminoethyl) imidazole is composed of an imidazole heterocycle and ethylamine side chain.  Histamine is a basic organic compound.  The imidazole N at position 3 is designated the pros (π) N, whereas the N at position 1 is termed the tele (τ) N.  Histamine is an achiral molecule. Structure of Histamine Saraswati Institute of Pharmaceutical 2 Sciences, Dhanap  STEREOCHEMISTRY OF HISTAMINE  Trans rotamer of histamine possesses affinity for both H1- and H2-receptors.  The gauche conformer is preferred for H3-receptors, but not for H1- and H2-receptors.  Rotamers are usually defined as low energy side chain conformations. Rotamers of Histamine Saraswati Institute of Pharmaceutical 3 Sciences, Dhanap  BIOSYNTHESIS OF HISTAMINE Histamine is synthesized in Golgi apparatus of its principal storage cells, mast cells, and basophils. Histamine is formed from the naturally occurring amino acid L-hisitidne. The release of histamine as one of the mediators of hypersensitivity reactions is initiated by the interaction of an antigen-IgE complex with the membrane of a histamine storage cell. Saraswati Institute of Pharmaceutical Biosynthesis Sciences,of Histamine Dhanap 4 HISTAMINE TAUTOMERS AND CATIONS  Histamine exists almost exclusively (96.6%) as the monocationic conjugate species (NH3+) at physiological pH (7.4).  At lower pHs, a higher percentage of the dicationic species exists.  Structure activity relationship studies suggest that the (NH3+) monocation is important for agonist activity at histamine receptors.  The Nτ-H tautomer of the histamine monocation is the pharmacophoric species at the H1- receptor. Saraswati Institute of Pharmaceutical 5 Sciences, Dhanap  HISTAMINE RECEPTORS LOCATION AND FUNCTIONS Sr. No Receptor Type Location of Receptor Functions 1 H1-Histamine  Smooth Muscle  Causes vasodilation Receptor  Endometrium  Bronchoconstriction  CNS  Smooth muscle activation  Primary receptor involved in allergic rhinitis symptoms and motion sickness. 2 H2-Histamine Parietal Cells Regulate gastric acid secretion. Receptor 3 H3-Histamine -- Reduce neurotransmitter release of Receptor Acetylcholine, histamine, norepinephrine and serotonin 4 H4-Histamine Thymus, small intestine, Unknown physiological role Receptor spleen, colon, basophils and bone marrow Saraswati Institute of Pharmaceutical 6 Sciences, Dhanap  FUNCTIONS OF HISTAMINE SUMMARY Histamine exhibits a wide variety of both physiological and pathological functions in different tissues and cells. (A) As a chemical mediator of hypersensitivity and allergic inflammatory reactions. (B) A major role in the regulation of gastric acid secretion. (c) An emerging role as a neurotransmitter in the CNS. Saraswati Institute of Pharmaceutical 7 Sciences, Dhanap  ANTIHISTAMINIC AGENTS (H1-RECEPTOR ANTAGONIST) Definition: Antihistaminic agents are drugs used to reduce or eliminate effects produced by histamine. Uses: Antihistaminics are widely used in the palliative treatment in allergic conditions like hay fever, urticaria, some forms of pruritus, rhinitis, conjunctivitis, nasal discharge, mild asthma etc. A few antihistaminics possess potent antiemetic action and hence are frequently employed in the prevention and treatment of motion sickness, nausea in pregnancy and postoperative vomiting. Side Effects: In general, the most common side effect of antihistaminics is sedation which may be followed by drowsiness, impaired alertness and retarded ability to perform jobs. Saraswati Institute of Pharmaceutical 8 Sciences, Dhanap  CLASSIFICATION OF H1-ANTAGONISTS First Generation H1-Antagonist (Classical Antihistamines) They are short to intermediate acting, more sedating and are likely to have more antimuscarinic side effects (blurred vision, dry mouth, urinary retention and constipation). A) Ethylenediamines  It is the earliest series of H1antihistamines.  Sedation is very common among the agents in this class General Structure Saraswati Institute of Pharmaceutical 9 Sciences, Dhanap B) Ethanolamine Ethers or Aminoalkyl ethers  Significant antimuscarinic side effects are observed among agents in this class. General Structure  Diphenhydramine is the prototype of this class.  It is used in treatment of Parkinsonism because of its central anticholinergic effect. Saraswati Institute of Pharmaceutical 10 Sciences, Dhanap  Dimenhydrinate is the combination of diphenhydramine and 8- chlorotheophylline.  It is used for the treatment of motion sickness.  8-chlorotheophylline was added in order to counteract drowsiness caused by diphenhydramine. Saraswati Institute of Pharmaceutical 11 Sciences, Dhanap  In Clemastine, the spacer is three carbon chain.  So it is not an ethanolamine ether but only an aminoalkyl ether.  Amino group is incorporated into pyrrolidine ring using one carbon of spacer as a part of the ring. Saraswati Institute of Pharmaceutical 12 Sciences, Dhanap C) PIPERAZINE (CYCLIZINE)  The piperazines are moderately potent antihistaminics with a relatively high potential to cause drowsiness and psychomotor and cognitive dysfunction.  The activity of the piperazine-type antihistaminics is characterized by a slow onset, but a long duration of action.  Piperazine dervvatives act on the medullary chemoreceptor trigger zone.  These agents have found significant use as antiemetics and antivertigo agents and in the treatment of motion sickness.  Some members of this series have exhibited a strong teratogenic potential (N-dealkylayed metabolites). General structure of Piperazine as antihistaminic agents Saraswati Institute of Pharmaceutical 13 Sciences, Dhanap  1-(diphenylmethyl)-4-methylpiperazine 1-(p-chloro--phenylbenzyl)-4-methylpiperazine Saraswati Institute of Pharmaceutical 14 Sciences, Dhanap  1-(p-chloro--phenylbenzyl)-4-(m-methylbenzyl)piperazine l-(p-tertbutylbenzyl)-4-(p-chloro--phenylbenzyl)piperazine Saraswati Institute of Pharmaceutical 15 Sciences, Dhanap D) Alkyl Amines These agents are characterized by a long duration of action and by a decreased incidence of central sedative side effects compared to the ethylenediamine and ethanolamine ether series. IUPAC Name of Chlorpheniramine 2-[p-Chloro-α-[2-(dimethylamino) ethyl] benzyl] pyridine Chlorpheniramine is widely used antihistamine for mild seasonal allergies. E-triprolidine is 1000 times more potent than its Z-isomer. Saraswati Institute of Pharmaceutical 16 Sciences, Dhanap E) Tricyclic derivatives The two aryl groups in the structure of antihistamines are bridged through a sulphur atom or through 2-carbon chain. Y=S X = C or N General Structure of tricyclic antihistamines The earliest potent tricyclic antihistamines were phenothiazines. Examples: Promethazine and Trimeprazine Saraswati Institute of Pharmaceutical 17 Sciences, Dhanap a) Phenothiazine Type of Tricyclic Antihistamines The antihistaminic phenothiazines contain a 2- or 3-carbon, branched alkyl chain as spacer. Whereas antipsychotic phenothiazines contain 3-carbon, unbranched alkyl chain as spacer. Promethazine has significant antiemetic and anticholinergic properties. It also has sedative-hypnotic properties and has been used to potentiate the effects of analgesic drugs. Trimeprazine is used as antipruritic agents in the treatment of urticaria. Saraswati Institute of Pharmaceutical 18 Sciences, Dhanap b) Other Tricyclic Antihistamines Cyproheptadine is an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes, sneezing. It works by blocking a natural substance histamine that our body secretes during allergic reaction. This drug also blocks another natural substance serotonin. Azatidine is pyridine analogue of cyproheptadine. This drug has effects similar to cyproheptadine. Saraswati Institute of Pharmaceutical 19 Sciences, Dhanap c) Miscellaneous Tricyclic Antihistamines Phenindamine is an indene. Phenindamine is an antihistamine. Phenindamine blocks the effects of the naturally occurring chemical histamine in human body. Saraswati Institute of Pharmaceutical 20 Sciences, Dhanap Second Generation H1-Antagonist (Non-Classical Antihistamines) They have improved H1 selectivity in periphery and have little or no sedative effects. They usually have less anticholinergic, antiadrenergic and antiserotonergic activity. They vary widely in structure but less so in pharmacological properties. The parent drug or its active metabolites have sufficiently long half-lives to account for the long duration of action. Most of the drugs are administered once daily. Examples: a) Terfenadine b) Astemizole c) Loratidine d) Cetirizine Saraswati Institute of Pharmaceutical 21 Sciences, Dhanap  Fexofenadine is acid metabolite of terfenadine. Terfenadine, fexofenadine and astemizole produce cardiac arrhythmias like cardiotoxic side effects. Saraswati Institute of Pharmaceutical 22 Sciences, Dhanap  Loratidine and its metabolite desloratidine are devoid of cardiotoxic side effects. Desloratidine is more potent H1 antagonist than loratidine. Saraswati Institute of Pharmaceutical 23 Sciences, Dhanap  Cetirizine is acid metabolite of hydroxyzine (piperazine class of first generation H1 antihistamines). It is widely used antihistamine. It is devoid of cardiotoxic side effects, but some drowsiness occurs. The Levo- isomer (Levocetirizine) has higher affinity than Dextro- isomer for the H1 receptor. Thus, antihistaminic properties of cetirizine probably are accounted by its Levo-isomer. Saraswati Institute of Pharmaceutical 24 Sciences, Dhanap Third-generation H1-antihistamines They are second-generation antihistamines but labeled as third- generation because the active enantiomer (levocetirizine) or metabolite (desloratadine and fexofenadine) derivatives of second-generation drugs are intended to have increased efficacy with fewer adverse drug reactions. Eutomer Distomer The eutomer is the chiral enantiomer having the desired pharmacological activity, e.g., as an active ingredient in a drug. The distomer, on the other hand, is the enantiomer of the eutomer which may have undesired bioactivity or may be bio-inert. Saraswati Institute of Pharmaceutical 25 Sciences, Dhanap Prevention of Histamine Release Example: Cromonyl Sodium Sodium cromoglycate inhibits the release of histamine and SRS-A in allergic reactions. It is mostly employed in the prophylactic treatment of asthma. It is used for bronchial asthma, as well as prevention of seasonal, constant, and physically caused asthma attacks and allergic rhinitis. Saraswati Institute of Pharmaceutical 26 Sciences, Dhanap Synthesis of Diphenhydramine IUPAC Nomenclature: N,N-dimethyl-(diphenylmethoxy)ethylamine Diphenhydramine is synthesized by the esterification of 2- dimethylaminoethanol with benzhydrylbromide Saraswati Institute of Pharmaceutical 27 Sciences, Dhanap Synthesis of Triprolidine IUPAC Nomenclature: 2-[(1E)-1-(4-methylphenyl)-3-(pyrrolidin-1-yl)prop-1-en-1-yl]pyridine Saraswati Institute of Pharmaceutical 28 Sciences, Dhanap Synthesis of Promethazine IUPAC Nomenclature: 10-[2-(Dimethylamino) propyl] phenothiazine monohydrochloride Saraswati Institute of Pharmaceutical 29 Sciences, Dhanap  Structure-Activity Relationship of H1-Antagonist The large number of potent antihistaminic agents belong to various defined chemical categories. However, it is now possible to derive some important conclusions with respect to their structural requirements for optimal activity and pharmacological actions. 1) Two aromatic groups (Ar1 and Ar2) are linked through a short chain (spacer) to a tertiary aliphatic amine. 2) The aromatic groups usually are phenyl, benzyl, thienyl, or pyridyl. Saraswati Institute of Pharmaceutical 30 Sciences, Dhanap 3. For maximum activity the carbon-chain between the O and N atoms or the N and N atoms must be the ethylene moiety, i.e., -CH2CH2-. However, a long or branched chain combination gives rise to a less potent analog. 4. It is interesting to observe that in the promethazine hydrochloride molecule the two carbon chain is linked with an iso-propyl moiety, but the presence of the phenothiazine group might exert better therapeutic effect on the molecules as such. 5. Introduction of a halogen atom viz, Cl, Br at the para-position of the phenyl function improves the antihistaminic activity of the parent molecule, e.g., pheniramine compared with, chloropheniramine and brompheniramine. 6. Amongst the ethylenediamine analogs many potent compounds have evolved due to the inclusion of various groups on the second N of the chain. Such groups may be either heterocyclic aromatic rings. 7. The nucleus of an antihistaminic must bear a minimum of two alkyl or aryl functions or an equivalent embeded in a polycyclic ring. Saraswati Institute of Pharmaceutical 31 Sciences, Dhanap 8) Antihistaminics exhibiting optical isomerism revealed that the dextro- isomer supersedes the levo-in their potency, e.g., dexchlorpherniramine, dexbrompheniramine and E isomer in triprolidine 9) Introduction of basic-cyclic ring system by altering the position of dimethyl amino group also enhances the antihistaminic activity, e.g., cyclizine, chlorcyclizine, meclizine etc. Saraswati Institute of Pharmaceutical 32 Sciences, Dhanap