Moyer, J. A.; Andree, T. H.; Haskins, J. T.; Husbands, G. E.M.; Muth, E. A. CNS Author Information

Seven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The O‐desmethyl compound Wy‐45,233, which is the major metabolite in man, had the greatest preclinical activity. This metabolite exhibited an antidepressant profile (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal β‐adrenergic subsensitivity) comparable to the parent drug, venlafaxine. This compound also inhibited serotonergic and noradrenergic firing rates like the parent compound, but with less potency. The cyclohexyl ring‐hydroxylated metabolite Wy‐47,877 and the N‐desmethyl metabolite Wy‐45, 494 were also active in reserpine hypothermia, but Wy‐45,494 was a weaker inhibitor of serotonin uptake and both metabolites were weaker inhibitors of norepinephrine uptake than Wy‐45,233. None of the seven metabolites tested exhibited significated binding at dopamine‐2, muscarinic cholinergic, α‐1‐adrenergic, histamine‐1, or opiate (μ) receptors. These results suggest that Wy‐45,233, the O‐desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side‐effect profile of venlafaxine.

A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.

AbstractA preclinical anxiolytic profile of the pyrimidinylpiperazinyl imide compound Wy‐47,846, is presented. In an effort to achieve an orally active, nonbenzodiazepine anxiolytic agent, the compound Wy‐47,846 was synthesized and examined in various preclinical neurochemical, psychopharmacological and neurophysiological tests. Wy‐47,846 displayed high affinity at the 5‐HT‐1A receptor binding site (Ki = 16.7 nM) and had weak‐to‐modest affinities for D‐2 and 5‐HT‐2 receptors. Wy‐47,846 also was effective in binding to the 5‐HT‐1A site in ex vivo receptor binding studies, but did not alter D‐2 binding under these conditions. Wy‐47,846 was also weak to inactive at displacing adrenergic (alpha‐1, alpha‐2, and beta), cholinergic, histamine H‐1, opiate, and benzodiazepine receptor radioligands from their respective binding sites. Wy‐47,846 reduced 5‐HT‐2 receptor binding following subacute (3 week) treatment. In both shelf‐jump and discrete trial conditioned avoidance tests, Wy‐47,846 reduced avoidance responding while increasing escape responses. No sedative effects were noted at behaviorally active doses. Like other nonbenzodiazepine anxiolytics, Wy‐47,846 also did not release the suppression of punished responding in shock‐suppressed drinking nor in Geller‐Seifter conflict experiments. Wy‐47,846 also potently inhibited serotonergic neuronal activity in the dorsal raphe nucleus, suggesting agonist activity at the 5‐HT‐1A receptor and increased noradrenergic neuronal activity in the locus coeruleus by an unknown mechanism. These findings support the characterization of Wy‐47,846 as a nonbenzodiazepine anxiolytic agent.

A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.

Wy 47,384 was examined in an extensive series of in vivo preclinical behavioral tests to determine its possible efficacy and side effect liability as a novel antipsychotic agent. Wy 47,384 was found to suppress avoidance responding following both i.p. and p.o. administration at doses that did not generally impair escape performance. Wy 47,384 also was found to be considerably more potent in antagonizing climbing behavior than stereotyped behavior produced by apomorphine. However, this compound demonstrated some cataleptogenic potential in catalepsy and global behavioral assessment tests. Wy 47,384 also produced limited sedation in motor activity, conflict, and rotorod ataxia tests, but the compound did not interact with ethanol. Wy 47,384 did not demonstrate preclinical anxiolytic activity in conflict behavior tests, and it did not show antidepressant effects in tests designed to assess beta‐adrenergic sensitivity. These studies show that Wy 47,384 is a specific putative antipsychotic agent with limited extrapyramidal and sedative side effect potential.

Several novel substituted gamma-carbolines were synthesized and examined in a series of in vitro and in vivo pharmacological tests to determine potential antipsychotic activity. Most compounds were orally active in blocking the conditioned avoidance response (CAR) in rats but did not antagonize apomorphine-induced stereotyped behavior. Compound 17 (Wy-47,384), a gamma-carboline with a 3-(3-pyridinyl)propyl side chain, was selected for development as an atypical antipsychotic agent because of its potent and selective profile in preclinical psychopharmacological tests. It blocked CAR in rats with an AB50 of 14 mg/kg po, showed weak affinity for the D2 receptor site (Ki = 104 nM), and showed differential potency in antagonizing apomorphine-induced stereotyped behavior (ED50 = 11 mg/kg ip) and climbing behavior (ED50 = 4 mg/kg ip). Such activities are suggestive of antipsychotic efficacy combined with a low potential for extrapyramidal side effect (EPS) liability.

Amperozide (AB Ferrosan, FG 5606), a new antiaggressive agent which exhibits a diverse preclinical profile of in vivo and in vitro activities, was examined to determine its acute effects on noradrenergic neurons of the locus coeruleus. The firing rates of all locus coeruleus neurons tested were increased by IV administration of amperozide. The amperozide-induced increase in locus coeruleus firing rate was similar in magnitude to that of an alpha-2 antagonist; however, amperozide was weaker than the alpha-2 antagonist yohimbine in reversing clonidine-induced inhibition of locus coeruleus neuronal activity and had weak affinity at the alpha-2 receptor ( K 1 = 3.5 μ M). Biochemically, amperozide displayed the most significant in vitro affinity at serotonin-2 receptors ( K 1 = 26 nM) and had low affinities at all other receptors examined. These properties are discussed in the context of amperozide's activation of the locus coeruleus as a part of its hypothetical mechanism of antiaggressive action.

A series of novel substituted beta-carbolines was synthesized and tested for potential antipsychotic activity. Several compounds displayed moderate antipsychotic activity in vitro and in vivo as determined by relevant receptor binding assays and behavioral tests. The effect of substituents on antipsychotic activity was examined. The beta-carbolines 10 and 19 containing 2-(2-pyridinyl)ethyl and 2-(2-quinolinyl)ethyl side chains were the most potent analogues, blocking discrete trial conditioned avoidance responding in rats with AB50's of 23 and 10 mg/kg, respectively. Both showed moderate activity at the D2 receptor sites, but they lacked oral activity. In contrast, the beta-carboline 13 containing the 4-(4-pyridinyl)butyl side chain exhibited oral activity in the discrete trial conditioned avoidance screen with an AB50 of 31 mg/kg. Most compounds did not antagonize apomorphine-induced stereotyped behavior, which is indicative of low potential for extrapyramidal side effect (EPS) liability.

The novel bicyclic compound Wy-45,030 [1-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclohexanol, hydrochloride] exhibited a neurochemical profile predictive of antidepressant activity. Like the tricyclic antidepressants, it inhibited rat brain imipramine receptor binding and synaptosomal monoamine uptake (dopamine as well as norepinephrine and serotonin). It did not inhibit monoamine oxidase. Unlike the tricyclic antidepressants, it was not antimuscarinic in the guinea pig ileum, nor did it have any appreciable affinity for brain α-1 adrenergic or histamine-1 binding sites. Wy-45,030 was also without affinity for α-2 or β adrenergic, benzodiazepine, serotonin-1, serotonin-2, dopamine-2, and opiate receptors. Such a profile is predictive of antidepressant activity devoid of the side-effects common to tricyclic therapy.

Abstract: Calmodulin activity in 68 discrete areas of rat brain, obtained by micropunch technique, was assessed by its capacity to activate a calmodulin‐sensitive form of phosphodiesterase. In general, the activity of calmodulin was higher in the telencephalon, limbic system, and hypothalamus than in the mesencephalon, pons, cerebellum, and medulla. However, there were substantial differences in calmodulin activity in discrete nuclei of each region. The regional distribution of calmodulin activity in rat brain does not appear to correlate with that of any of the known putative neurotransmitters or peptides.

Wy-45,030 and Wy-45,881 block the uptake of norepinephrine and serotonin in rat brain synaptosomal preparations and share several in vivo and in vitro effects with known tricyclic antidepressants. To further characterize their activity, these compounds were compared to desipramine and ciramadol in electrophysiological studies of their acute effects on noradrenergic neuronal activity. All four compounds inhibited locus coeruleus neuronal activity with a rank order of potency of desipramine Wy-45,881 > Wy-45,030 > ciramadol. Administration of the α-adrenergic blocking drug, piperoxane, increased locus coeruleus firing rate after desipramine, Wy-45,030 and Wy-45,881. Pretreatment with naloxone prevented the reduction in locus coeruleus impulse flow observed after ciramadol administration but had no effect on the inhibition produced by Wy-45,030 and Wy-45,881, like classical antidepressants, appear to inhibit locus coeruleus neuronal firing by potentiating neuroinhibitory transmission of locus coeruleus neurons by blocking the uptake of norepinephrine into presynaptic terminals.