A conformational study of four 5-HT1A (serotonin) receptor ligands ((R-(-)-methiothepin, spiperone, (S)-(-)-propranolol, and buspirone) led to the definition of a pharmacophore and a three-dimensional map of the 5-HT1A antagonist recognition site. These models were used to design new compounds and successfully predict their potency, stereospecificity, and selectivity. For example, 8-[4-[(1,4-benzodioxan-2-ylmethyl)amino] butyl]-8-azaspiro[4.5]decane-7,9-dione (1, MDL 72832) has nanomolar affinity (pIC50 = 9.14) for the 5-HT1A binding site in rat frontal cortex. As predicted, the S-(-) enantiomer of 1 was more active than its R-(+) enantiomer (pIC50 = 9.21 and 7.66, respectively) and a naphthalene analogue of 1 displayed the expected improved selectivity.

Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated.

In the rabbit isolated perfused heart, dolasetron (MDL 73,147) was found to be a potent (PA, = 9.8) antagonist at 5-hydroxytryptamine3 (5-HT,) receptors present on sympathetic nerve terminals. In anesthetized rats, intravenous (iv), intraduodenal (id), or oral administration of dolasetron blocked the von Bezold-Jarisch reflex elicited by iv injection of 5-HT; the iv ED,, was approximately 3 p,g/kg and following a dose of 140 p,g/kg iv the reflex was abolished for >85 min.The compound displayed no significant affinity for 5-HT1, 5-HT2, or a variety of other radioligand binding sites at a concentration of 10 FM. In conscious ferrets, dolasetron suppressed the vomiting induced by an iv injection of the anti-cancer drug cisplatin (10 mg/kg). Intravenous doses (0.05-0.5 mglkg) administered 30 min before and 45 min after cisplatin were clearly anti-emetic and single oral doses of 0.5 or 2 mg/kg, given 30 min prior to cisplatin, were also effective. Minimal changes in the behavior of mice were observed at doses up to 100 mg/kg given ip or subcutaneously (sc). It is concluded that dolasetron i s a potent, selective, and reversible antagonist at neuronal 5-HT3 receptors, which i s well tolerated. The compound i s effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug-induced vomiting. o 1993 Wiley-Liss, Inc.

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SL1 4AUCyclisations of 2-phenylethyl isocyanate (2), ( + ) -I -methyl-2-phenylethyI isocyanate (3). and 2,2-diphenylethyl isocyanate (4) have been studied using polyphosphoric acid, aluminium chloride, boron trifluoride-diethyl ether, and triethyloxonium tetrafluoroborate. Depending on the reaction conditions, triethyloxonium tetrafluoroborate, forexample, notonlygavetheexpected isoquinolones (1 4)-(I 6) and other expected products, but in two cases, also gavethe2-N-(2-phenylethyl)formamidyl-3,4-dihydroisoquinolin-l (2H)-ones ( 9) and (1 0). Theisoquinolone (1 5) w a s alkylated with triethyloxonium tetrafluoroborate or methyl fluorosulphonate to give 1 -ethoxy-( 7) or 1met h oxy -3 -met h y I -3,4 -d i hydro i soq u i no I in e ( 8), respective I y . INTRAMOLECULAR cyclisation of isothiocyanates providesa useful synthesis of isoquinolines,l thienopyridines,2 ben~azepines,~ and thieno[3,2-~]azepines.~ Thus, for example, cyclisation of 2-phenylethyl isothiocyanate with triet hyloxonium tetrafluoroborate gives 1 -ethylthio-3,4-dihydroisoquinoline (5) .l These results prompted us to study cyclisations of the corresponding isocyanates with triethyloxonium tetrafluoroborate and other reagents.At the start of our work 6,7-diniethoxy-3,4-dihydroisoquinolin-1 ( 2 H ) -one (corydaldine) had been synthesised by cyclisation of homoveratryl isocyanate with phosphoryl chloride and polyphosphoric acid while the latter reagent had been used also to synthesise other 3,4dihydroisoquinolin-1 (2H)-ones.6 Since then, polyphosplioric acid and boron trifluoride-diethyl ether * have been used successfully to cyclise p-arylethyl isocyanates. A recently reported two-stage treatment with phosphorus oxychloride and tin(rv) chloride appears to be