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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.

The effect of the chemically novel dopaminergic agonist, ciladopa (AY-27,110) was studied on rotational behavior in unilaterally 6-OHDA-lesioned rats and on stereotyped behavior in normal animals during and after chronic treatment. Ciladopa, at a 1.25 mg/kg SC daily dose, was administered for 4 and 6 weeks to the lesioned and normal animals, respectively. This dose was threshold for turning but subthreshold with respect to stereotypy. Both behaviors were evaluated weekly during chronic treatment and biweekly for 11 weeks after its discontinuation in response to doses previously shown to elicit turning and stereotypy. The chronic administration of ciladopa enhanced rotational behavior considerably more and with an earlier onset than stereotypy, although the duration of behavioral supersensitivity after cessation of treatment was the same. These results indicate that behaviors mediated by supersensitive or intact dopamine receptors are differently affected by chronic dopamine agonist treatment. The results are discussed in relation to their potential therapeutic implications and current concepts of agonist-induced supersensitivity.

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.

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.

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.

A series of N-aralkyltroponylpiperazine derivatives were synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine (DA) pathway and to suppress elevated serum prolactin levels. The compounds were compared to bromocriptine. Some of the more potent analogues were also assayed for their binding affinity to dopamine (DA) and alpha 1-adrenergic receptors. The results established that the potency of some of the compounds were comparable or superior to that of bromocriptine indicated that potent dopaminergic activity was dependent on the presence of both a substituted phenyl and a troponylpiperazine moiety, and confirmed that the dopaminergic activity depends on relative and absolute stereochemistry.

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.

Butaclamol is a member of a new chemical class for which antipsychotic activity in humans has been demonstrated. Butaclamol, a racemate, has been resolved into its optical isomers and a separation of activities was found to occur between the (+) and (-) enantiomers. The present experiments show that at doses ranging from 0.1 to 0.3 mg/kg the (+) enantiomer abolished amphetamine-induced (a) stereotyped behavior and (b) rotational behavior in rats with unilateral lesions in the substantia nigra. It also inhibited the lever-pressing response in the continuous (Sidman) avoidance procedure, blocked discriminated avoidance behavior, and decreased ambulation and rearing in the open field. In contrast, the (-) enantiomer was devoid of behavioral activity at 100-500 times larger doses. At considerably higher doses (+)-butaclamol antagonized epinephrine-induced mortality. Again, the (-)-butaclamol was devoid of this activity as well. The significance of absolute optical specifity manifested by a neuroleptic drug is discussed in the light of dopaminergic and adrenergic mechanisms.

A comparison is described between the activity of the melanocyte-stimulating hormone release inhibiting factor (MIF) and those of five synthetic tripeptide analogues of MIF. The comparison was based upon the ability of the compounds to potentiate the behavioral effects of L-dopa in mide and to antagonize fluphenazine-induced catalepsy in rats. Three of the tripeptides potentiated L-dopa in a manner similar to that of MIF. All of the synthetic analogues antagonized fluphenazine after a single dose although their potency and their duration of action differed. MIF was active in the latter test only following chronic administration. The possible mechanism of action and the potential clinical applicability of the tripeptides are briefly discussed.

The development and degree of supersensitivity to the locomotor stimulant effect of apomorphine were studied in rats which had been rendered hypokinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus. Up to 2 days after surgery the effect of apomorphine was comparable in lesioned and normal rats, indicating that dopaminergic supersensitivity did not develop over this short period. As the duration between the 6-hydroxydopamine injections and time of testing with apomorphine increased, the animals became progressively more sensitive to the stimulant effects of apomorphine. Pretreatment with butaclamol reduced the effect of apomorphine in a dose-dependent manner. A high dose of clozapine also antagonized the effect of apomorphine, but a low dose potentiated it. No inhibition was observed following administration of the alpha-adrenergic antagonist, phenoxybenzamine, or the beta-adrenergic antagonist, propranolol. The 5HT antagonist methysergide and the anticholinergic drug, scopolamine potentiated the effects of apomorphine.l These studies suggest that the apomorphine-induced ambulation in hypokinetic rats is primarily mediated through dopaminergic mechanisms but both serotonergic and cholinergic mechanisms exert modulating influences.

A series of alkyltroponylpiperazine derivatives was synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine pathway. The compounds were compared to bromocriptine. The results indicate that dopaminergic activity is very sensitive to small changes in the troponylpiperazine moiety.

Butaclamol hydrochloride (AY-23,028) is a member of a new chemical class for which antipsychotic activity in humans has recently been demonstrated. The compound antagonized amphetamine-induced stereotyped behavior in rats, amphetamine toxicity in aggregated mice and apomorphine-induced emesis in dogs. It depressed both discriminated avoidance and continuous lever-pressing behavior in rats and inhibited ambulation and rearing in the open field. At higher doses, AY-23,028 induced catalepsy. Adrenergic blocking activity, measured by the antagonism of epinephrine-induced mortality, was weak. These pharmacological actions are characteristic of neuroleptic drugs. In the dose range where the aforementioned effects were observed AY-23,028 did not antagonize either the tetrabenazine-induced ptosis or the tremorine syndrome and did not cause either hypothermia or ataxia. The potency and onset of action of AY-23,028 were comparable to those of fluphenazine but AY-23,028 was of longer duration. The results are discussed in relation to current concepts of neuroleptic mechanisms.