Antonio Vong

Characterization of the binding of [3H]‐SB‐204269, a radiolabelled form of the new anticonvulsant SB‐204269, to a novel binding site in rat brain membranes

1 SB‐204269 (trans‐(+)‐6‐acetyl‐4S‐(4‐fluorobenzoylamino)‐3,4‐dihydro‐2,2‐dimethyl‐2H‐benzol[b]pyran‐3R‐ol, hemihydrate) shows potent anticonvulsant activity in a range of animal seizure models, with a lack of neurological or cardiovascular side‐effects. The profile of the compound suggests that it may have a novel mechanism of action. This study describes the characteristics of a binding site for [3H]‐SB‐204269 in rat forebrain membranes. 2 Specific [3H]‐SB‐204269 binding was saturable and analysis indicated binding to a homogenoeous population of non‐interacting binding sites with a dissociation constant (KD) of 32±1 nM and a maximum binding capacity (Bmax) of 253±18 fmol mg−1 protein. Kinetic studies indicated monophasic association and dissociation. Binding was similar in HEPES or Tris‐HCl buffers and was unaffected by Na+, K+, Ca2+ or Mg2+ ions. Specific binding was widely distributed in brain, but was minimal in a range of peripheral tissues. 3 Specific [3H]‐SB‐204269 binding was highly stereoselective, with a 1000 fold difference between the affinities of SB‐204269 and its enantiomer SB‐204268 for the binding site. The affinities of analogues of SB‐204269 for binding can be related to their activities in the mouse maximal electroshock seizure threshold (MEST) test of anticonvulsant action. 4 None of the standard anticonvulsant drugs, phenobarbitone, phenytoin, sodium valproate, carbamazepine, diazepam and ethosuximide, or the newer anticonvulsants, lamotrigine, vigabatrin, gabapentin and levetiracetam, showed any affinity for the [3H]‐SB‐204269 binding site. A wide range of drugs active at amino acid receptors, Na+ or K+ channels or various other receptors did not demonstrate any affinity for the binding site. 5 These studies indicate that SB‐204269 possesses a specific CNS binding site which may mediate its anticonvulsant activity. This binding site does not appear to be directly related to the sites of action of other known anticonvulsant agents, but may have an important role in regulating neuronal excitability.

New quinoline NK3 receptor antagonists with CNS activity.

Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.

Novel 2,3,4,5-tetrahydro-1H-3-benzazepines with high affinity and selectivity for the dopamine D3 receptor.

Starting from the dopamine D3 receptor antagonist SB-277011 1, a series of 2,3,4,5-tetrahydro-1H-3-benzazepines has been identified with high affinity for the dopamine D3 receptor and selectivity over the D2 receptor. The 3-acetamido-2-fluorocinnamide derivative 20 gave high D3 receptor affinity (pKi 8.4) with 130-fold selectivity over the 2, receptor.

Novel 1,2,3,4-tetrahydroisoquinolines with high affinity and selectivity for the dopamine D3 receptor.

Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.

Stereochemical differentiation of anticonvulsant and antihypertensive effects in 4-(fluorobenzoylamino)-benzopyrans

Abstract Replacement of the 2-pyrrolidinone group of cromakalim 1 by the fluorobenzoylamino group has introduced anticonvulsant activity. It is particularly noteworthy that this activity is found predominantly in the 3R,4S enantiomeric series. In contrast, antihypertensive activity is restricted to the 3S,4R enantiomeric series.

Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor.

Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).

Discovery of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (GSK163090), a Potent, selective, and orally active 5-HT1A/B/D receptor antagonist.

In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.

Stereochemical preferences and requirement for the 3-hydroxyl group in novel anticonvulsant 4-fluorobenzoylamino benzopyrans

Abstract A cis 3 S ,4 S isomer, derived stereospecifically from an anticonvulsant trans 3 R ,4 S -( para -fluorobenzoylamino)-benzopyran using the DAST reagent, has been shown to possess anticonvulsant properties. In contrast the cis 3 R ,4 R enantiomer did not possess anticonvulsant properties but caused blood pressure to fall.