Syntheses of 2-[(3,5-dimethyl-4-methoxypyridyl)alkyl]-benzothiazolidine derivatives as a potential gastric H+/K(+)-ATPase inhibitor

A series of 2-[(3,5-dimethyl-4-methoxypyridyl)alkyl]benzothiazolidine derivatives were synthesized and tested their inhibitory effects on gastric H+/K(+)-ATPase. Compound 4d exhibited potent in vitro inhibitory activity.     

Specific inhibition of Na+,K(+)-ATPase activity by atractylon, a major component of byaku-jutsu, by interaction with enzyme in the E2 state

Acute myocardial infarction (AMI) is known to be associated with a complex neuroendocrine activation, especially concerning sympathetic and renin-angiotensin systems, cortisol, atrial natriuretic peptide and endothelin. Results of our study show that the vasoactive intestinal peptide (VIP), also, is early involved in the neuroendocrine activation occurring in AMI. Plasma concentration of VIP, significantly increased in AMI patients within 6 hours after the onset of chest pain, soon decreased and remained below than normal along the first week. At the 14th day of the AMI, plasma levels of VIP returned into the normal range. A significant increase of VIP plasma concentration is detectable in the first hours of AMI in survived as compared with died patients. The phenomenon seems to be a suitable process to provide an endogenous support to the ischemic heart and to counteract the negative effects of other neuroendocrine activated factors.     

7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymeth yl)chromen -4-one (abaperidone, FI-8602)

A series of novel 7-[3-(1-piperidinyl)propoxy]chromenones was synthesized and tested as potential antipsychotics in several in vitro and in vivo assays. The compounds possessed good affinity for D2 receptors, together with a greater affinity for 5-HT2 receptors, a profile which has been proposed as a model for atypical antipsychotics. Several agents also displayed a high potency in the climbing mice assay on oral administration, suggesting a potent antipsychotic effect as compared to reference standards. Compound 23 was selected for further pharmacological evaluation. Induction of catalepsy and inhibition of stereotypies weaker than standards, along with a lower increase in serum prolactin levels, were indicative of a potential atypical profile for this compound. From these results, 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl )chromen- 4-one (23, abaperidone) has been proposed for clinical evaluation in humans as a potential atypical antipsychotic.     

Effects of the new angiotensin receptor antagonist dipotassium (Z)-2-[[5-ethyl-3-[2''-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl-1,3,4-thiadiazoline-2-ylidene]aminocarbonyl]-1-cy clopentencarbox ylate on experimental cardiac hypertrophy and acute left ventricular failure

A 26-year-old woman was admitted to our hospital because of dyspnea and fever one day after taking medicines for the common cold. A chest roentgenogram and a computed tomogram revealed diffuse patchy infiltrates in both lung fields. Examination of a specimen obtained by transbronchial lung biopsy showed thickening of alveolar walls and infiltration of eosinophils. Bronchoalveolar lavage fluid had many eosinophils. DLST was positive for Bufferin, which the patient took one day before the dyspnea and fever began. We believe that this patient's pulmonary disease was caused by Bufferin. We should realize that this widely used analgesic can cause acute eosinophilic lung disease. The patient was not given corticosteroids, and her condition improved soon after she stopped taking Bufferin.     

The angiotensin receptor antagonist 2-ethoxy-1-[[2'-(1H- tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV11974) attenuates the tubuloglomerular feedback response during NO synthase blockade in rats

Nitric oxide (NO) produced in the juxtaglomerular apparatus may regulate the tubuloglomerular feedback (TGF) response. The inhibition of intrinsic NO results in significant renal hemodynamic changes, a phenomenon similar to that observed after angiotensin II (A-II) administration. We measured stop-flow pressure (Psf) during loop perfusion with artificial tubular fluid in Sprague-Dawley rats to establish whether alterations in TGF responsiveness during NO inhibition depend on the action of endogenous A-II. The NO synthase blocker N omega-nitro-L-arginine-methyl-ester (L-NAME: 10 mg/kg i.v.) significant increased TGF responsiveness, defined as the change in Psf on increasing loop flow from 0 to 40 nl/min compared with control (delta Psf: -21.3 +/- 2.6 vs. -9.7 +/- 0.6 mm Hg, P < .001). After concomitant treatment with the nonpeptide A-II type 1 receptor antagonist 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxic acid (CV11974: 1 mg/kg i.v.) and L-NAME, the TGF response was attenuated significantly (delta Psf: -7.6 +/- 1.9 mm Hg, P < .001). On the other hand, Psf in the absence of loop perfusion was increased similarly by L-NAME treatment in the presence (53.7 +/- 2.2 mm Hg) or absence of CV11974 (Psf 50.7 +/- 3.2 mm Hg). These results suggest that augmentation of the TGF response by endogenous NO inhibition depends, at least in part, on the intrinsic A-II activity.     

Study of the non-steady state electrogenic transport of sodium ions by Na+,K(+)-ATPase by the capacitance measurement method

The goal of work was to investigate the electrogenic transport of Na ions by Na+,K(+)-ATPase in membrane fragments absorbed on a planar bilayer lipid membrane. The photorelease of ATP from an inactive precursor, caged ATP, induced a transient current and changes in the net system capacitance measured during the application of an alternating voltage. The increments of capacitance (delta c) decreased with the increase in the frequency of the applied voltage. The characteristic frequency F0 of the steepest slope of the curve significantly decreased in solutions with high ionic strength (either NaCl or choline chloride), in which Na+ transport is decelerated. The value of delta c correlated with the total charge delta q transported across the membrane. The capacitance increments decreased when the Na+ concentration in solution decreased. At a concentration below 2 mM the increment became negative. The increase in membrane capacitance can be attributed to the charge relaxation process inside the protein, as discovered in the cells by other methods. The characteristic frequency F0 depends on the time constants of charge redistribution. The nonlinear dependences of delta c on delta q were explained by a voltage bias across the membrane fragments resulting from pumping. The potentials corresponding to the maximum capacitance change were similar to the midpoint potentials of the equilibrium charge distribution and depended on the Na+ concentrations in solution. The model enabled also the determination of the total capacitance of the active region of a lipid membrane with the adsorbed protein containing membrane fragments.     

Synthesis and pharmacological evaluation of 1-methyl-5-[substituted-4 (3H)-oxo-1,2,3-benzotriazin-3-yl]-1H-pyrazole-4-acetic acid derivatives

Several new 1-methyl-5-[substituted-4-oxo-1,2,3-benzotriazin-3-yl] -1H-pyrazole-4-acetic acids and their ethyl ester derivatives were prepared. The compounds were tested for analgesic and antiinflammatory activities, acute toxicity, ulcerogenic effect, and as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), since it is claimed that the inhibition of such an enzyme predicts in vivo antiinflammatory activity. Some compounds were more active than phenylbutazone in the phenylbenzoquinone and acetic acid peritonitis tests, and equiactive to the same drug in the carrageenin paw edema test. All the compounds inhibited the 3 alpha-HSD, but no correlation was observed with the paw edema inhibition values. The compounds proved to possess marginal or no ulcerogenic effect, as well as low systemic toxicity.     

(3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: a conformationally restricted analogue of the NR2B subtype-selective NMDA antagonist (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)- 1-propanol

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptor-cis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1- yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.     

Synthesis and trazodone-like analgesic activity of 4-phenyl-6-aryl-2-[3-(4-arylpiperazin-1-yl)propyl]pyridazin -3-ones

A series of 4,6-diaryl pyridazinones, chemically related to trazodone, ws synthesized and evaluated for analgesic activity. With ED50 values ranging from 8.4 to 46.7 mg kg(-1) i.p. in the phenylbenzoquinone-induced writhing test (PBQ test), most compounds were several times more potent than acetaminophen (ED50 = 231.3 mg kg(-1) i.p.) and noramidopyrine (ED50 = 68.5 mg kg(-1) i.p.). A multiple linear regression analysis demonstrated a correlation between antinociceptive activity and lipophilicity, as well as electronic and steric factors. The most active pyridazinones 2c and 2j exhibited minimal sedative and neurotoxic effects at the dose of 25 mg kg(-1) i.p. They were devoid of activity in the hot plate test and their analgesic activity was not significantly reversed by naloxone in the PBQ test. The antinociceptive response induced by morphine (0.15 mg kg(-1) s.c.) in the PBQ test was greatly potentiated by 2c and 2j administered at the low doses of 1 and 2.5 mg kg(-1) i.p., respectively. On the other hand, their analgesic effects were enhanced synergistically by 5-hydroxytryptophan combined with carbidopa. All these data imply that a significant part of the antinociceptive effect induced by 2c and 2j may involve both opioid and serotonergic pathways. In addition, these two pyridazinones did not exhibit any antidepressant properties in the forced swimming test, nor did they potentiate yohimbine-induced toxicity.     

N-(2-pyridinyl)-2-[2(3H)-benzazolone-3-yl]acetamides: synthesis, antinociceptive and anti-inflammatory activity

Eighteen N-(2-Pyridyl)-2-[2(3H)-benzazolone-3-yl]acetamide derivatives have been synthesized. The chemical structure of the compounds have been elucidated by elemental analysis, IR and 1H NMR spectral data and their antinociceptive and anti-inflammatory activities were tested in mice. Compound VII o has shown the highest antinociceptive activity, and VII g, j, k, r exhibited relatively high antinociceptive activity. In addition, compounds VII d, f, j, p showed statistically significant anti-inflammatory activity.     

N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand

A series of new 1-aryl-4-alkylpiperazines containing a terminal benzamide fragment or a tetralin-1-yl nucleus on the alkyl chain were synthesized and tested for binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (17) emerged since it exhibited very high affinity for dopamine D4 receptor (IC50 = 0.057 nM) with selectivity of >10 000 for the D4 versus the D2 receptor; compound 17 was also selective versus serotonin 5-HT1A and adrenergic alpha1 receptors.     

Development of orally active oxytocin antagonists: studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl]piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.     

S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride

The novel benzoindane S 18126 possessed > 100-fold higher affinity at cloned, human (h) D4 (Ki = 2.4 nM) vs. hD2 (738 nM), hD3 (2840 nM), hD1 (> 3000 nM) and hD5 (> 3000 nM) receptors and about 50 other sites, except sigma1 receptors (1.6 nM). L 745,870 similarly showed selectivity for hD4 (2.5 nM) vs. hD2 (905 nM) and hD3 (> 3000 nM) receptors. In contrast, raclopride displayed low affinity at hD4 (> 3000 nM) vs. hD2 (1.1 nM) and hD3 receptors (1.4 nM). Stimulation of [35S]-GTPgammaS binding at hD4 receptors by dopamine (DA) was blocked by S 18126 and L 745,870 with Kb values of 2.2 and 1.0 nM, respectively, whereas raclopride (> 1000 nM) was inactive. In contrast, raclopride inhibited stimulation of [35S]-GTPgammaS binding at hD2 sites by DA with a Kb of 1.4 nM, whereas S 18126 (> 1000 nM) and L 745,870 (> 1000 nM) were inactive. As concerns presynaptic dopaminergic receptors, raclopride (0.01-0.05 mg/kg s.c. ) markedly enhanced DA synthesis in mesocortical, mesolimbic and nigrostriatal dopaminergic pathways. In contrast, even high doses (2. 5-40.0 mg/kg s.c.) of S 18126 and L 745,870 were only weakly active. Similarly, raclopride (0.016 mg/kg i.v.) abolished inhibition of the firing rate of ventrotegmental dopaminergic neurons by apomorphine, whereas even high doses (0.5 mg/kg i.v.) of S 18126 and L 745,870 were only weakly active. As regards postsynaptic dopaminergic receptors, raclopride potently (0.01-0.3 mg/kg s.c.) reduced rotation elicited by quinpirole in rats with unilateral lesions of the substantia nigra, antagonized induction of hypothermia by PD 128, 907, blocked amphetamine-induced hyperlocomotion and was effective in six further models of potential antipsychotic activity. In contrast, S 18126 and L 745,870 were only weakly active in these models (5.0-> 40.0 mg/kg s.c.). In six models of extrapyramidal and motor symptoms, such as induction of catalepsy, raclopride was likewise potently active (0.01-2.0 mg/kg s.c.) whereas S 18126 and L 745,870 were only weakly active (10.0-80.0 mg/kg s.c.). In freely moving rats, raclopride (0.16 mg/kg s.c.) increased levels of DA by + 55% in dialysates of the frontal cortex. However, it also increased levels of DA in the accumbens and striatum by 70% and 75%, respectively. In contrast to raclopride, at a dose of 0.16 mg/kg s.c. , neither S 18126 nor L 745,870 modified frontal cortex levels of DA. However, at a high dose (40.0 mg/kg s.c.), S 18126 increased dialysate levels of DA (+ 85%) and noradrenaline (+ 100%), but not serotonin (+ 10%), in frontal cortex without affecting DA levels in accumbens (+ 10%) and striatum (+ 10%). In conclusion, S 18126 and L 745,870 behave as potent and selective antagonists of cloned, hD4 vs. other dopaminergic receptor types in vitro. However, their in vivo effects at high doses probably reflect residual antagonist actions at D2 (or D3) receptors. Selective blockade of D4 receptors was thus associated neither with a modification of dopaminergic transmission nor with antipsychotic (antiproductive) or extrapyramidal properties. The functional effects of selective D4 receptor blockade remain to be established.     

Dual inhibition of human type 4 phosphodiesterase isostates by (R, R)-(+/-)-methyl 3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3- methyl-1-pyrrolidinecarboxylate

Purified recombinant human type 4 phosphodiesterase B2B (HSPDE4B2B) exists in both a low- and a high-affinity state that bind (R)-rolipram with Kd's of ca. 500 and 1 nM, respectively [Rocque, W. J., Tian, G., Wiseman, J. S., Holmes, W. D., Thompson, I. Z., Willard, D. H., Patel, I. R., Wisely, G. B., Clay, W. C., Kadwell, S. H., Hoffman, C. R., and Luther, M. A. (1997) Biochemistry 36, 14250-14261]. Since the tissue distribution of the two isostates may be significantly different, development of inhibitors that effectively inhibit both forms may be advantageous pharmacologically. In this study, enzyme inhibition and binding of HSPDE4B2B by (R, R)-(+/-)-methyl 3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-1-pyrrolidin ecarboxylate (1), a novel inhibitor of phosphodiesterase 4 (PDE 4), were investigated. Binding experiments demonstrated high-affinity binding of 1 to HSPDE4B2B with a stoichiometry of 1:1. Inhibition of PDE activity showed only a single transition with an observed Ki similar to the apparent Kd determined by the binding experiments. Deletional mutants of HSPDE4B2B, which have been shown to bind (R)-rolipram with low affinity, were shown to interact with 1 with high affinity, indistinguishable from the results obtained with the full-length enzyme. Bound 1 was completely displaced by (R)-rolipram, and the displacement showed a biphasic transition that resembles the biphasic inhibition of HSPDE4B2B by (R)-rolipram. Theoretical analysis of the two transitions exemplified in the interaction of (R)-rolipram with HSPDE4B2B indicated that the two isostates were nonexchangeable. Phosphorylation at serines 487 and 489 on HSPDE4B2B had no effect on the stoichiometry of binding, the affinity for binding, or the inhibition of the enzyme by 1. These data further illustrate the presence of two isostates in PDE 4 as shown previously for (R)-rolipram binding and inhibition. In contrast to (R)-rolipram, where only one of the two isostates of PDE 4 binds with high affinity, 1 is a potent, dual inhibitor of both of the isostates of PDE 4. Kinetic and thermodynamic models describing the interactions between the nonexchangeable isostates of PDE 4 and its ligands are discussed.     

4-[(1H-imidazol-4-yl) methyl] benzamidines and benzylamidines: novel antagonists of the histamine H3 receptor

A series of amidine substituted phenyl-, benzyl-, and phenethylimidazoles based on the known H3 agonist SK&F 91606 (4) has been synthesized and tested as ligands for the histamine H3 receptor. Insertion of a phenyl ring between the imidazole ring and the amidine moiety produces antagonists. The benzyl series was found to be the most potent and was further investigated. Compounds 9c and 18 (entries 5 and 12, Table 1) are potent ligands for the H3 receptor with K(i) values of 16 nM and 7.2 nM respectively. In vivo, both compounds were shown to be equipotent to thioperamide (2), the standard H3 antagonist.     

Studies on anti-inflammatory agents. V. Synthesis and pharmacological properties of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5- [4-(methylsulfinyl)phenyl]pyrazole and related compounds

A series of novel 1,5-diphenylpyrazole derivatives bearing hydrophilic substituents was prepared. The anti-inflammatory and analgesic activities of these compounds were evaluated by using the adjuvant arthritis and Randall-Selitto assays in rats, and the structure-activity relationships were studied. The optimal compound was 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (10) with oral ED50 values of 0.31 and 2.6 mg/kg on adjuvant-induced arthritis and carrageenin-induced foot edema, respectively. Compound 10 showed analgesic activities not only toward inflamed paw but also toward normal paw (ED30 = 0.55 and 1.8 mg/kg, respectively) in the Randall-Selitto assay, and moreover, 10 was effective in the tail-pinch assay (ED50 = 21 mg/kg) similarly to morphine. The asymmetric synthesis and pharmacological properties of the enantiomers of 10 are also reported.     

Antitumor activity of the R- and S-enantiomers of RS-2-[[hydroxy[[2-[ (octadecyloxy)methyl]tetrahydrofuran-2-yl]methoxy]-phosphinyl]oxy]-N, N,N,-trimethylethylaminium hydroxide inner salt

The R- and S-enantiomers of 2-[[hydroxyl[[2-[(octadecyloxy) methyl]tetrahydrofuran-2-yl]methoxy]-phosphinyl]oxy]-N,N,N,- trimethylethylaminium hydroxide salt (SRI 62-834) have been evaluated in several assays to determine potential antitumor activity. The S-enantiomer showed slightly greater cytotoxic activity than the R- or RS-forms against several murine tumor cell lines. In the mouse Meth A fibrosarcoma model, the S-enantiomer was ca. 4 times more effective than the R-isomer in controlling size of tumor growth and increasing the number of survivors.     

Synthesis and beta-adrenoreceptor blocking activity of [[3-(alkylamine)-2-hydroxypropyl]oximino]pyridines and O[3-(alkylamine)-2-hydroxypropyl]methylpyridine ketone oximes derivatives

[[3-(alkylamine)-2-hydroxypropyl]-2-oximino]pyridines and O-[3-(alkylamine)-2-hydroxypropyl]methylpyridine ketone oximes 5a-o were synthesized by a solid-liquid phase-transfer reaction, and their beta-adrenoreceptor blocking activity was evaluated in vitro and in vivo. The replacement of the aryl linked to the oximic carbon of the (methylenaminoxy)methyl moiety with the bioisoster pyridine ring produced a decrease of the beta-adrenergic blocking activity. The polarization of the oximic group, derived from the electron-withdrawing action of the nitrogen atom, is more evident for the 2-oxyminopyridine derivative 5d. But also conformational parameters may play an important role in the variation of activity of the compounds 5d, 5l and 5n. The replacement of the hydrogen linked to the oximic carbon with a methyl group increased the activity of the compounds 5a, 5i, 5m and 5o. The methyl could allow a delocalization of the partial positive charge present on the oximic carbon, but also its lipophilicity contributed to the increment of binding to the receptor site. None of the compounds showed high beta 1 or beta 2 selectivity in vitro. The (R) and (S) isomers of the compound 5a were synthesized and obtained with enantiomeric ratio 7:3 and 6:4, respectively. The binding tests and the pharmacological in vivo results confirmed the in vitro data.     

The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function both in vitro and in vivo

5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 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] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.