Resolved 6,7,8,9-tetrahydro-N,N-dimethyl-3H-benz[e]indol-8-amine: central dopamine and serotonin receptor stimulating properties.

The enantiomers of 6,7,8,9-tetrahydro-N,N-dimethyl-3H-benz[e]indol-8- amine (1a) were prepared and tested for their actions on central dopamine and serotonin (5-HT) receptors. The dopaminergic effects were shown to reside in the (1)-R enantiomer. It was shown that compound 1a and its (+)-R enantiomer possess potent central 5-HT1A receptor stimulating properties.

Synthesis and biological evaluation of 4,6-diethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-4-acetic acid, an isomer of etodolac.

The synthesis of 4,6-diethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-4-acetic acid, an isomer of the antiinflammatory agent etodolac, is described. The compound was found to have an ED50 of 3 mg/kg po in the rat curative adjuvant arthritis assay, and an IC50 of 50 nM for inhibiting prostaglandin production in cultured chondrocytes.

Structure-activity relationships among analogues of pemedolac, cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indo le-1-a cetic acid, a potent analgesic agent.

The syntheses of analogues of pemedolac (cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indol e-1-acetic acid), a potent analgesic, are described. They were tested for analgesic and antiinflammatory effects in vivo and for inhibition of prostaglandin production in vitro. Analysis of structure-activity relationships shows that analgesic activity in this series is associated with 1S-cis stereochemistry, the presence of a pi-system (allyl or benzyl) at position 4, and a log P value greater than 4.0.

Etodolac, a novel antiinflammatory agent. The syntheses and biological evaluation of its metabolites.

The syntheses of five metabolites of the antiinflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid) are described, viz. 6-hydroxyetodolac, N-methyletodolac, 4-ureidoetodolac, 8-(1'-hydroxy)etodolac, and 4-oxoetodolac. These syntheses were used to confirm the identities of the metabolites. The metabolites themselves, as well as the previously reported metabolite 7-hydroxyetodolac, were tested in a rat adjuvant edema model and in vitro for their capacity to block prostaglandin production in chondrocyte cells. All either were inactive or possessed only marginal activity. The isolation of N-methyletodolac and 4-oxoetodolac from human and rat urine, respectively, is also described.

Synthesis and analgesic activity of pemedolac (cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]ind ole-1- acetic acid).

The synthesis of cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indole -1-acetic acid, pemedolac (USAN), is described. This compound has been found to be a potent analgesic agent in primary screening. Pemedolac has been resolved and the active (+)-enantiomer assigned a 1S,4R absolute configuration on the basis of a crystallographic analysis of its (S)-(-)-borneol ester.

Ligand-receptor interactions via hydrogen-bond formation. Synthesis and pharmacological evaluation of pyrrolo and pyrido analogues of the cardiotonic agent 7-hydroxycyclindole.

The syntheses of N,N-dimethyl-6,7,8,9-tetrahydro-3H,10H-pyrrolo[3,2-a] carbazol-7-amine (8), N,N-dimethyl-7,8,9,10-tetrahydro-11H-pyrido[3,2-a] carbazol-8-amine (9a), and the N,N,11-trimethyl analogue (9b) are described. The in vitro inotropic activity of these compounds, as well as the known cardiotonics amrinone and 7-hydroxycyclindole (7), was investigated. Compound 8, a pyrrolo analogue of 7, was devoid of inotropic activity, while the pyrido analogues 9 were equiactive to 7 and amrinone. These results suggest that the hydroxyl group of 7 functions as an H-bond acceptor, rather than a donor, and that on interaction of 7, and the pyrido analogues 9, with a common receptor, an orbital occupied by one of the oxygen lone pair electrons of 7 must assume the same orientation as the orbital occupied by the pyridine nitrogen lone pair.

Synthesis and analgesic evaluation of 4-(2-heptyloxy)-7-[(Z)-(3-hydroxycyclohexyl)]indole: a caveat on indole-phenol bioisosterism.

The synthesis of 4-(2-heptyloxy)-7-[(Z)-(3-hydroxycyclohexyl)]indole (7) is described. Compound 7 was tested for analgesic properties in the phenylbenzoquinone writhing test and was found to be essentially devoid of activity. In contrast, cis-3-[4-(2-heptyloxy)-2-hydroxyphenyl]cyclohexanol (8), the analogue in which the pyrrolo ring is replaced by a hydroxyl group, had an ED50 of 8.3 mg/kg, sc, in the same model. The absence of bioisosterism between the pyrrolo ring and the phenolic hydroxyl group, in this instance, is discussed in terms of the circumstances that control the manifestation of bioisofunctionality between a pyrrolo ring and a phenolic hydroxyl group, which functions as a hydrogen-bond donor.

Indole-phenol bioisosterism. Synthesis and antihypertensive activity of a pyrrolo analogue of labetalol.

The synthesis of 5-[hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-1H-indole-7- carboxamide, 5, a pyrrolo analogue of labetalol, is described. Compound 5 was found to reduce blood pressure in spontaneously hypertensive rats with an ED50 of 5 mg/kg po, without causing any decrease in heart rate. Isolated tissue studies with 5 shows that it is a nonselective beta-adrenoceptor antagonist and that it is a weaker alpha-adrenoceptor antagonist with a relative selectivity for alpha 1-receptors. Additionally, the compound displayed significant beta-adrenoceptor intrinsic sympathomimetic activity. Evidence is presented that the beta-adrenoceptor antagonist and agonist properties of 5 are mediated via hydrogen-bond formation with the receptor.

Drug design via pharmacophore identification. Dopaminergic activity of 3H-benz[e]indol-8-amines and their mode of interaction with the dopamine receptor.

The design and synthesis of a series of 3H-benz[e]indol-8-amines are described. Two of the compounds are potent, orally active dopaminergic agents as established by their ability to induce contralateral turning in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway, to induce ambulation in rats rendered akinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus, and to antagonize reserpine-induced catalepsy in mice. The dopamine agonist activity of the 3H-benz[e]indol-8-amines establishes that a pyrrolo ring and a phenolic hydroxyl group can interact similarly with the dopamine receptor and provides evidence for the existence of a hydrogen-bond acceptor nucleus on the dopamine receptor macromolecule that is involved in the behavioral manifestations of dopamine agonists.

Etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid): a potent antiinflammatory drug. Conformation and absolute configuration of its active enantiomer.

The active (+) enantiomer of the antiinflammatory agent etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid) has been assigned an S absolute configuration on the basis of a crystallographic analysis of the (S)-(-)-borneol ester of (-)-etodolac, and the conformation of etodolac has been determined by a crystallographic analysis of (+/-)-etodolac. Analyses of the solid-state conformation, as well as energy-minimized conformations obtained by molecular mechanics calculations, have failed to provide a basis for identifying a probable receptor-site conformation.

Resolution of etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers.

Etodolac, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, a clinically effective analgesic and antiinflammatory agent, has been resolved via a chromatographic separation of its diastereoisomeric esters with (-)-borneol. The effects of the enantiomers were studied in vitro on prostaglandin synthetase and on adjuvant-induced arthritis in rats. The biochemical and pharmacological results show that virtually all of the effects of etodolac are due to the (+) enantiomer.

Mapping the dopamine receptor. 1. Features derived from modifications in ring E of the neuroleptic butaclamol.

Several analogues of the neuroleptic agent butaclamol, having modifications in the ring E region of the molecule, have been synthesized. Pharmacological evaluation identified two of the analogues as being equipotent to butaclamol, namely, anhydrobutaclamol (8) and deoxybutaclamol (9a). The molecular structures of both the active and inactive analogues were analyzed and the results have been used for mapping the central dopamine receptor. The existence of a previously proposed lipophilic accessory binding site on the receptor macromolecule has been confirmed. Its minimum dimensions, as well as its locus with respect to the primary binding sites, have been defined. A receptor model incorporating the above features is proposed.

Mapping the dopamine receptor. 2. Features derived from modifications in the rings A/B region of the neuroleptic butaclamol.

Several analogues of the neuroleptic agent butaclamol having modifications in the rings A/B region of the molecule have been synthesized. Pharmacological evaluation identified the benzo[5,6]cyclohepta analogue 2b, isobutaclamol, as being equipotent to butaclamol. The molecular structure of this compound has been analyzed, and the results have been used for mapping the central dopamine receptor. A planar catechol primary binding site, composed of alpha and beta regions, has been identified and its minimal dimensions deduced. Its locus with respect to the nitrogen location site and its complementary hydrogen bond donor site has been specified. Using a Cartesian coordinate system, a receptor model is proposed which incorporates the above-mentioned features. The receptor model has been used to rationalize the observed chirality of the central dopamine receptor.

Neuroleptics related to butaclamol. An investigation of the effects of chlorine substituents on the aromatic rings.

The synthesis of analogues of the antipsychotic drug butaclamol bearing chloro substituents on the benzene rings is described. On the basis of a perceived topographical similarity of a putative chlorophenylethylamine pharmacophore present in these analogues and in VUFB-10032 and doclothepin, agents related to octoclothepin which do not induce catalepsy, they have been tested for "noncataleptic" neuroleptic activity. None of the butaclamol analogues exhibit this type of activity. Depending on the position of the chlorine, the analogues either retained butaclamol-like activity or were inactive.

Neuroleptics related to butaclamol. Synthesis and some psychopharmacological effects of a series of 3-aryl analogues.

The synthesis and some pharmacological effects of 16 3-aryl analogues of butaclamol, a new antipsychotic drug, are described. The animal models were predictive of neuroleptic activity as well as side effects commonly associated with neuroleptic therapy. The results indicate that the 3-substituent plays a critical role with regard to the potency of the compounds as well as to their tendencies to induce extrapyramidal side effects and/or hypotension.

Syntheses and primary pharmacological screening of tandamine and related tetrahydrothiopyranoindoles with potential antidepressant properties.

A series of novel 1,3,4,9-tetrahydro-1-methyl-thiopyrano-[3,4-b]indole-1-ethanamines has been synthesized and examined for effects on reserpine-induced ptosis and reserpine-induced hypothermia in mice. One member of the series, the 9-ethyl-N,N-dimethyl derivative V (tandamine), was selected for further studies in regard to its possible use as an antidepressant agent. Tandamine has been resolved, and the levorotatory enantiomer was found to be more active than the racemic compound. The N-desmethyl derivative XIII, a metabolite of tandamine, has been prepared. The 5-ethyl-1,3,4,5-tetrahydro-N,N,1-trimethylthiopyrano[4,3-b]indole-1-ethanamine XXI, an analog of tandamine with the isomeric ring system, has also been synthesized and evaluated. In the primary pharmacological screening and in the drug-interaction studies with reserpine, tetrabenazine, and tremorine, tandamine was compared to the clinically effective tricyclic antidepressants--desipramine, imipramine, and amitriptyline. Tandamine was more effective than these agents in several screening procedures indicative of potential antidepressant activity.

Cycloalkanoindoles. 2. 1-Alkyl-1,2,3,4-tetrahydrocarbazole-1-ethanamines and related compounds. Potential antidepressants.

The synthesis is described of a series of cycloalkanoindoles, comprising tetrahydrocarbazoles, a cyclopentindole, and a cycloheptindole, all bearing an ethanamine side chain at position 1. The acute toxicities of these compounds were evaluated, as well as their potential antidepressant properties, using tests based on the prevention of ptosis induced by reserpine and tetrabenazine. 9-Ethyl-N,N1-trimethyl-1,2,3,4-tetrahydrocarbazole-1-ethanamine (AY-24 614) was found to be the most potent analogue, having an ED50 of 0.12 mg/kg ip in preventing reserpine-induced ptosis in mice and an ED50 at 3.3 mg/kg ip in preventing tetrabenazine-induced ptosis in rats.