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 5HT1 , 5HT1 and 5HT1 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 5HT 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 5HT , 5HT and 5HT receptors with similar high affinity.