Dimers of 5HT1 ligands preferentially bind to 5HT1B/1D receptor subtypes.
New dimers of known 5HT1 ligands (5HT, 1-NP or 8-OH-DPAT) have been prepared and evaluated at human cloned 5HT1B, 5HT1D and 5HT1A receptors. Binding experiments show that all these dimers have better affinities at 5HT1B/1D receptors than their corresponding monomeric ligands. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5HT1B receptor show that hetero-bivalent ligands [combining an agonist (5HT) with an antagonist (1-NP)] behave as partial agonists while the intrinsic activity of bivalent antagonists (combining two 1-NP residues) was found to be spacer dependent. Surprisingly enough, the dimer of 8-OH-DPAT 6 binds to 5HT1A, 5HT1B and 5HT1D receptors with similar high affinity.
Perez
M
M
Medicinal Chemistry Division, Centre de Recherche Pierre FABRE, Castres, France.
Jorand-Lebrun
C
C
Pauwels
P J
PJ
Pallard
I
I
Halazy
S
S
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D012702:Serotonin Antagonists / Q000737:chemistry / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism
C470302:HTR1B protein, human; D008024:Ligands; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C048241:1-(1-naphthyl)piperazine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000242:Cyclic AMP