5HT1D receptors are found at low levels in the basal ganglia (globus pallidus, substantia nigra, caudate putamen), the hippocampus, and in the cortex.[6]
Structure
5HT1D receptor is a
G protein linked receptor that activates an
intracellular messenger cascade to produce an inhibitory response by decreasing cellular levels of cAMP.[7][8] The 5HT1D is a
7-TM receptor. A large intercellular loop between TM-5 and TM-6 is believed to be associated with coupling to a second messenger. Agonists might bind in a manner that utilizes an
aspartate residue in TM-3 and residues in the TM-4, TM-5 and TM-6.[9] A human clone containing an intronless
open reading frame was found to encode 377 amino acids of the 5HT1D receptor. The gene has been localized on chromosome 1, region 1p34.3-36.3 [10][11]
Ligands
Agonists
Molecular modelling has provided a picture of the
agonistic binding site of 5HT1D. The
amino acid residues within the receptor binding site region have been identified. This is a valuable guide to design potential 5HT1D receptor agonists.
When
sumatriptan binds there is major conformational change in both ligand and receptor in the binding pocket.[12]
^Hoyer, D., 2019. Serotonin receptors nomenclature. The Serotonin System, pp. 63–93.
^Millan, M.J., et al., Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends in Pharmacological Sciences, 2008. 29(9): pp. 454–464.
^Goadsby, P.J., Serotonin 5-HT1B/1D receptor agonists in migraine - Comparative pharmacology and its therapeutic implications. Cns Drugs, 1998. 10(4): p. 271-286.
^Lippincott, W. W., Lemke, T. L., Williams, D. A., Roche, V. F., & Zito, S. W. (2013). Foye's Principles of Medicinal Chemistry: Lippincott Williams & Wilkins: 368-376.
^Bremner, D. H.; Ringan, N. S.; Wishart, G. (1997). "Modeling of the agonist binding site of serotonin human 5-HT1A, 5-HT1Dα and 5-HT1Dβ receptors". European Journal of Medicinal Chemistry. 32 (1): 59–69.
doi:
10.1016/S0223-5234(97)84362-0.
^Glennon RA, Hong SS, Dukat M, Teitler M, Davis K (Sep 1994). "5-(Nonyloxy)tryptamine: a novel high-affinity 5-HT1D beta serotonin receptor agonist". Journal of Medicinal Chemistry. 37 (18): 2828–30.
doi:
10.1021/jm00044a001.
PMID8071931.
^Xu YC, Schaus JM, Walker C, Krushinski J, Adham N, Zgombick JM, Liang SX, Kohlman DT, Audia JE (Feb 1999). "N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist". Journal of Medicinal Chemistry. 42 (3): 526–31.
doi:
10.1021/jm9805945.
PMID9986723.
External links
"5-HT1D". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Hamblin MW, Metcalf MA, McGuffin RW, Karpells S (Apr 1992). "Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity". Biochemical and Biophysical Research Communications. 184 (2): 752–9.
doi:
10.1016/0006-291X(92)90654-4.
PMID1315531.
Hamblin MW, Metcalf MA (Aug 1991). "Primary structure and functional characterization of a human 5-HT1D-type serotonin receptor". Molecular Pharmacology. 40 (2): 143–8.
PMID1652050.
Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (Sep 1991). "Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor". Genomics. 11 (1): 225–7.
doi:
10.1016/0888-7543(91)90125-X.
PMID1662665.
Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, Simons MJ, Dumont JE, Vassart G (May 1989). "Selective amplification and cloning of four new members of the G protein-coupled receptor family". Science. 244 (4904): 569–72.
Bibcode:
1989Sci...244..569L.
doi:
10.1126/science.2541503.
PMID2541503.
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (Jul 1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nature Genetics. 22 (3): 231–8.
doi:
10.1038/10290.
PMID10391209.
S2CID195213008.
Bergen AW, van den Bree MB, Yeager M, Welch R, Ganjei JK, Haque K, Bacanu S, Berrettini WH, Grice DE, Goldman D, Bulik CM, Klump K, Fichter M, Halmi K, Kaplan A, Strober M, Treasure J, Woodside B, Kaye WH (2003). "Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa". Molecular Psychiatry. 8 (4): 397–406.
doi:
10.1038/sj.mp.4001318.
PMID12740597.
S2CID22413624.
5HT1D receptors are found at low levels in the basal ganglia (globus pallidus, substantia nigra, caudate putamen), the hippocampus, and in the cortex.[6]
Structure
5HT1D receptor is a
G protein linked receptor that activates an
intracellular messenger cascade to produce an inhibitory response by decreasing cellular levels of cAMP.[7][8] The 5HT1D is a
7-TM receptor. A large intercellular loop between TM-5 and TM-6 is believed to be associated with coupling to a second messenger. Agonists might bind in a manner that utilizes an
aspartate residue in TM-3 and residues in the TM-4, TM-5 and TM-6.[9] A human clone containing an intronless
open reading frame was found to encode 377 amino acids of the 5HT1D receptor. The gene has been localized on chromosome 1, region 1p34.3-36.3 [10][11]
Ligands
Agonists
Molecular modelling has provided a picture of the
agonistic binding site of 5HT1D. The
amino acid residues within the receptor binding site region have been identified. This is a valuable guide to design potential 5HT1D receptor agonists.
When
sumatriptan binds there is major conformational change in both ligand and receptor in the binding pocket.[12]
^Hoyer, D., 2019. Serotonin receptors nomenclature. The Serotonin System, pp. 63–93.
^Millan, M.J., et al., Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends in Pharmacological Sciences, 2008. 29(9): pp. 454–464.
^Goadsby, P.J., Serotonin 5-HT1B/1D receptor agonists in migraine - Comparative pharmacology and its therapeutic implications. Cns Drugs, 1998. 10(4): p. 271-286.
^Lippincott, W. W., Lemke, T. L., Williams, D. A., Roche, V. F., & Zito, S. W. (2013). Foye's Principles of Medicinal Chemistry: Lippincott Williams & Wilkins: 368-376.
^Bremner, D. H.; Ringan, N. S.; Wishart, G. (1997). "Modeling of the agonist binding site of serotonin human 5-HT1A, 5-HT1Dα and 5-HT1Dβ receptors". European Journal of Medicinal Chemistry. 32 (1): 59–69.
doi:
10.1016/S0223-5234(97)84362-0.
^Glennon RA, Hong SS, Dukat M, Teitler M, Davis K (Sep 1994). "5-(Nonyloxy)tryptamine: a novel high-affinity 5-HT1D beta serotonin receptor agonist". Journal of Medicinal Chemistry. 37 (18): 2828–30.
doi:
10.1021/jm00044a001.
PMID8071931.
^Xu YC, Schaus JM, Walker C, Krushinski J, Adham N, Zgombick JM, Liang SX, Kohlman DT, Audia JE (Feb 1999). "N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist". Journal of Medicinal Chemistry. 42 (3): 526–31.
doi:
10.1021/jm9805945.
PMID9986723.
External links
"5-HT1D". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Hamblin MW, Metcalf MA, McGuffin RW, Karpells S (Apr 1992). "Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity". Biochemical and Biophysical Research Communications. 184 (2): 752–9.
doi:
10.1016/0006-291X(92)90654-4.
PMID1315531.
Hamblin MW, Metcalf MA (Aug 1991). "Primary structure and functional characterization of a human 5-HT1D-type serotonin receptor". Molecular Pharmacology. 40 (2): 143–8.
PMID1652050.
Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (Sep 1991). "Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor". Genomics. 11 (1): 225–7.
doi:
10.1016/0888-7543(91)90125-X.
PMID1662665.
Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, Simons MJ, Dumont JE, Vassart G (May 1989). "Selective amplification and cloning of four new members of the G protein-coupled receptor family". Science. 244 (4904): 569–72.
Bibcode:
1989Sci...244..569L.
doi:
10.1126/science.2541503.
PMID2541503.
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (Jul 1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nature Genetics. 22 (3): 231–8.
doi:
10.1038/10290.
PMID10391209.
S2CID195213008.
Bergen AW, van den Bree MB, Yeager M, Welch R, Ganjei JK, Haque K, Bacanu S, Berrettini WH, Grice DE, Goldman D, Bulik CM, Klump K, Fichter M, Halmi K, Kaplan A, Strober M, Treasure J, Woodside B, Kaye WH (2003). "Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa". Molecular Psychiatry. 8 (4): 397–406.
doi:
10.1038/sj.mp.4001318.
PMID12740597.
S2CID22413624.