Despite only modest homology between h5-HT1B and h5-HT1D receptor amino acid sequences, these receptors display a remarkably similar pharmacology. To date there are few compounds which discriminate between these receptor subtypes and those with some degree of selectivity, such as ketanserin, have greater affinity for other 5-HT receptor subtypes. We now report on two compounds, SB-216641 (N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide) and BRL-15572 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1-diphenyl-2-propanol), which display high affinity and selectivity for h5-HT1B and h5-HT1D receptors, respectively. In receptor binding studies on human receptors expressed in CHO cells, SB-216641 has high affinity (pKi = 9.0) for h5-HT1B receptors and has 25-fold lower affinity at h5-HT1D receptors. In contrast, BRL-15572 has 60-fold higher affinity for h5-HT1D (pKi = 7.9) than 5-HT1B receptors. Similar affinities for these compounds were determined on native tissue 5-HT1B receptors in guinea-pig striatum. Functional activities of SB-216641 and BRL-15572 were measured in a [35S]GTPgammaS binding assay and in a cAMP accumulation assay on recombinant h5-HT1B and h5-HT1D receptors. Both compounds were partial agonists in these high receptor expression systems, with potencies and selectivities which correlated with their receptor binding affinities. In the cAMP accumulation assay, results from pK(B) measurements on the compounds again correlated with receptor binding affinities (SB-216641, pK(B) = 9.3 and 7.3; BRL-15572, pK(B) = <6 and 7.1, for h5-HT1B and h5-HT1D receptors respectively). These compounds will be useful pharmacological agents to characterise 5-HT1B and 5-HT1D receptor mediated responses.

1 Human 5-HT 1B (h5-HT 1B ) and human 5-HT 1D (h5-HT 1D ) receptors show remarkably similar pharmacology with few compounds discriminating the receptors. We report here on a novel compound, SB-224289 (1'-Methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3-f]indole-3,4'-piperidine] oxalate), which has high a nity for h5-HT 1B receptors (pK 1 =8.16+0.06) and displays over 75 fold selectivity for the h5-HT 1B receptor over all other 5-HT receptors including the h5-HT 1D receptor and all other receptors tested thus far. 2 Functional activity of SB-224289 was measured in a [ 35 S]GTPgS binding assay on recombinant h5-HT 1B and h5-HT 1D receptors expressed in Chinese Hamster Ovary (CHO) cells. SB-224289 displayed negative intrinsic activity at both receptors with higher potency at h5-HT 1B receptors. SB-224289 caused a rightward shift of agonist concentration response curves consistent with competitive antagonism and generated a nities comparable with those obtained from competition radioligand receptor binding studies. 3 SB-224289 potentiated [ 3 H]5-HT release from electrically stimulated guinea-pig cerebral cortical slices to the same extent as as the non-selective 5-HT 1 antagonist methiothepin. SB-224289 also fully reversed the inhibitory e ect of exogenously superfused 5-HT on electrically stimulated release. 4 Using SB-224289 as a tool compound, we con®rm that in guinea-pig cerebral cortex the terminal 5-HT autoreceptor is of the 5-HT 1B subtype.

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We conclude that PTSD in a Vietnam veteran father increases the risk specifically for PTSD in his sons and daughters.