Define Histamine receptor

1. Histamine is a biogenic amine involved in local immune responses, in
regulating physiological function in the gut. It also acts as a neurotransmitter.
Histamine is derived from the decarboxylation of the amino acid L-
histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase.
Histamine controls a multitude of physiological functions by activating
specific receptors on target cells.
Histamine acts as one of the major inflammatory mediators in allergic
challenges.
Histamine exerts its effects by binding to four different histamine
receptors (H1-H4), which all belong to the large family of G protein-
coupled receptors (GPCR).
Histamine
HISTAMINE

2. Type Location Function
H1 histamine receptor Found on smooth muscle,
endothelium, and central nervous
system tissue
Causes vasodilation, broncho
constriction, smooth muscle
activation, separation of
endothelial cells , and pain and
itching due to insect stings; the
primary receptors involved in
allergic rhinitis symptoms and
motion sickness
H2 histamine receptor Located on parietal cells Primarily stimulate gastric acid
secretion
H3 histamine receptor - Decreased neurotransmitter
release: histamine, acetylcholine,
norepinephrine, serotonin
H4 histamine receptor Found primarily in the thymus,
small intestine, spleen, and colon.
Unknown physiological role.
HISTAMINE RECEPTORS

3. Research and development of H1 ligands largely has focused on antagonists that
are used for their anti-allergic effects in the periphery. Recent understanding of the
clinical importance of H1 receptors in brain, however, suggests the
pharmacotherapeutic potential of H1 agonists in neurodegenerative and
neuropsychiatric disorders.
Despite the therapeutic importance of the H1 receptor for many years the 3D-
model of the H1 receptor protein were not known. In view of this and our
continuing interest on antihistamines H1 where different models derived from SAR,
2D & 3D-QSARs (1-7) have been developed.
 The homology model of the H1 receptor based on the crystal structure of bovine
rhodopsin as template has been constructed that has been compared with the
recently published crystal structure of human H1 (pdb id: 3RZE).
1. M. Saxena, et al. Bioorg. and Med. Chem. 14, 8249-8258, 2006.
2. M. Saxena, et al. Infection, 33, 198, 2005.
3. S. Gaur, P. Prathipati, M. Saxena & A.K. Saxena. Med. Chem. Res., 13, 724-745, 2004
4. A.K. Saxena, M. Saxena, H. Chi & M. Wiese. Med. Chem. Res., 3 (1993), 201.
5. G.K. Patnaik, A.K. Saxena, M. Saxena, J. Rao & R.C. Srimal. Ind. J. Exp. Biol., 30 (1992),144.
6. M. Saxena, et al. J. Med. Chem., 33 (1990), 2970-2976.
7. A.K. Saxena, S.Ram, M.K. Dhaon, M. Saxena, (late) P.C. Jain, G.K. Patnaik & N. Anand.
Ind. J. Chem., 22B (1983), 1224.
H1 RECEPTOR

4. Complementarity between octahydro-
pyrazinopyridoindole (thick line) and
diphenhydramine (dotted line)
Model for H1-receptor binding sites
Superimposition of 6 (dotted line) and 1 (thick line) in the
same orientation as in HASL
Alignment Techniques

5. The Apex 3D model
Catalyst generated pharmacophore
The Apex 3D model generate two sites namely biophoric sites (BS) and secondary sites (SS).
The biophoric sites are present in all molecules in the dataset i.e. they are the minimum pharmacophoric
requirement for a molecule to be active at a particular target.
The secondary sites are responsible for modulating the activity i.e. depending upon them activity at a
particular target may increase or decrease.
Apex 3D and Catalyst

6.  The Apex 3D model generated three biophoric sites and six secondary sites.
The biophoric sites are generated around the phenyl ring of the benzoyl fragment, phenyl ring
of the indole fragment and pyrazine nitrogen next to the two carbon chain linker.
The catalyst generated model depicted two hydrophobes (blue), one positive ionizable (red)
and one hydrogen bond acceptor (green) feature.
However our Apex 3D model generated only three biophoric sites that signify the acceptor
feature generated in catalyst is not essential for activity and hence the two hydrophobes and a
positive ionizable feature is the pharamacophoric requirement for a compound to be active at the
human H1 receptor.

7. ECL1
ECL2
ECL3
ICL1
ICL2
ICL3
Structure of G-protein coupled receptor
Extracellular N-terminal
Seven transmembrane -helices
Three extracellular loops
(ECL1, ECL2, ECL3)
Three intracellular loops
(ICL1, ICL2, ICL3)
Intracellular C-terminal

8. Homology modeling of Human H1 receptor
A homology model of HRH1 has been generated by using the crystal structure of Bovine
Rhodopsin as template (pdb id: 1F88). The sequence alignment was done by using Clustal W
server. Ten models were built using the software MODELLER. These models were refined using
state of the art techniques
The primary sequences of the H1 receptor (HRH1) and Bovine Rhodopsin were taken from
Swiss-Prot (www.expasy.org) accession number P35367,P02699 respectively. Structural data for
Bovine-Rhodopsin was obtained from the Protein Data Bank ( www.rscb.org)
The long IC3 loop of the HRH1 was removed as it has no homologous sequence in Bovine
Rhodopsin from the alignment.
Sequence alignment was done using Clustal W sequence alignment server. This alignment was
further adjusted manually.
The overall Sequence identity and similarity with the template was found to be 18.2% and
14.94% respectively

9. Sequence Alignment

10. Free Internet Resources
ICM browser for Windows XP platform.
http://www.molsoft.com/icm_browser.html
Discovery Studio 3.1 Visualizer for Windows XP platform.
http://accelrys.com/products/discovery-studio/visualization-download.php
Ligand scout 2.0 for Windows XP platform.
www.inteligand.com

11. Acknowledgement
 Mr. A.S. Kushwaha.
 Stuti Gaur.
THANK YOU