Design, synthesis, and evaluation of metabolism-based analogues of haloperidol incapable of forming MPP+-like species.

The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [K(i)(D2) = 33, K(i)(D3) = 200, K(i)(D4) = 11 nM; K(i)(D2)/K(i)(D4) = 3] and 9 [K(i)(D2) = 44, K(i)(D3) = 170, K(i)(D4) = 24 nM; K(i)(D2)/K(i)(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.

A review of chemical agents in the pharmacotherapy of addiction.

Chemical substance abuse has tormented mankind throughout history. A number of chemical approaches have been employed in an attempt to treat chemical addiction. Unfortunately, most of these have proven unsuccessful though several chemical entities have been shown to be moderately effective. The naturally occurring alkaloid ibogaine has been reported to interrupt the cravings for alcohol, cocaine and opiates. Other alkaloids from Tabernanthe iboga, such as ibogamine and tabernanthine, provide insight into the structure activity relationship at the different receptors believed to be involved in addiction. The synthetic iboga alkaloid congener, 18-MC, also shows potential as an anti-addictive agent without the hallucinogenic effects of ibogaine. Additionally, acamprosate, BP 897, GBR12909, lofexidine and memantine have shown promising results in the treatment of addiction. All of these leads provide a start for the medicinal chemist to design anti-addictive agents, since currently no drugs are approved in the U.S. for the treatment of addictions to cocaine, methamphetamine, other stimulants or PCP.

A review of cancer chemopreventive agents.

In the late 20(th) century, the treatment of cancer began to include its prevention. Today, compounds exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogen dependent tumors. Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors. Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to determine the chemopreventive activity of new compounds are quite often activities of enzymes. The identification of those individuals at high risk is still in its infancy and presents a troubling dilemma.

Detection of a neurotoxic quaternary pyridinium metabolite in the liver of haloperidol-treated rats.

Various theories have been proposed in the past to explain the side effects associated with haloperidol treatment. In this study, we tested the hypothesis that in vivo biotransformation of haloperidol to a quaternary pyridinium metabolite might contribute to some of these effects. Administration of haloperidol (IP or by gavage) to male Wistar rats results in its biotransformation to a butyrophenone quaternary pyridinium metabolite similar to MPTP metabolism to MPP+. The corresponding methyl quaternary pyridinium compound was not detected in the liver or brain of the rats used in this study. The proposed methyl quaternary pyridinium compound and the observed butyrophenone metabolite were tested for neurotoxicity in a frog model of MPTP action and were found to have neurotoxic effects, although the methyl quaternary pyridinium compound was much more toxic.

Freezing action of a metabolite of haloperidol in frogs.

In vivo metabolism studies led to the identification of a previously proposed metabolite of haloperidol, 4-(4'-chlorophenyl)-4-piperidinol (CPPO), in the liver of a haloperidol-treated rat. However, the secondary metabolites of CPPO that we have proposed were not observed in this study. Neurotoxicity studies in frogs, which have been used to detect N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) action, showed that CPPO did not mimic the neurotoxicity of MPTP but caused a delayed and persistent freezing action in Rana pipiens frogs. It is proposed that this action may contribute to some of the delayed side-effects associated with haloperidol therapy.

Pharmacologic and toxicologic effects of di(beta-phenylisopropyl)amine (DPIA) in rats and mice.

1. Di(beta-phenylisopropyl)amine (DPIA) given i.p. to mice and rats in sublethal doses caused increased motility, mild stereotypic behavior and suppression of food intake. Repeated daily doses led to enhanced motor stimulation, and in one group, 40% lethality, indicating development of "reverse tolerance". Brain monoamine modifiers prevented DPIA-induced motor activity. 2. Treatment with toxic i.p. doses of DPIA enabled determination of the LD50, which was 106.8 mg/kg for isolated mice and 89.7 mg/kg for mice kept in aggregation after dosing. Possible antidotal agents given before a high DPIA dose (LD50) protected significantly against lethality. 3. Combinations of DPIA with (+)-amphetamine in mice at lethal doses showed a subadditive synergism. 4. Effects of DPIA on the cardiovascular system, both i.v. in anesthetized rats and in isolated atrial preparations, were mainly opposite to those of (+)-amphetamine, namely decreases in blood pressure, force of contraction and heart rate.

N- and 2-substituted N-(phenylsulfonyl)glycines as inhibitors of rat lens aldose reductase.

A variety of N-(phenylsulfonyl)-N-phenylglycines 5, N-(phenylsulfonyl)-2-phenylglycines 6, and N-(phenylsulfonyl)anthranilic acids 7 were prepared as analogues of the N-(phenylsulfonyl)glycine 1 aldose reductase inhibitors. In the rat lens assay, several derivatives of 5 display greater inhibitory activity than the corresponding glycines 1, suggesting that N-phenyl substitution enhances affinity for aldose reductase. Enzyme kinetic evaluations of the 4-benzoylamino analogues of 5 and 1 demonstrate that these compounds produce inhibition by the same mechanism. However, the significant differences in relative inhibitory potencies between compounds of series 5 and 1 may indicate that these compounds do not interact with the inhibitor binding site in precisely the same manner. Evaluation of the individual enantiomers of series 6 reveals that the S isomers are substantially more active than the corresponding R isomers. Also, with the exception of the naphthalene analogue 6n, the S stereoisomers of this series display greater inhibitory potencies than the glycines 1. The anthranilates 7 generally are less active than the glycines 1, demonstrating that direct incorporation of an aromatic ring in the glycine side chain may result in a decrease in affinity for aldose reductase.

2-Amino- and 2-guanidino-1,2,3,4-tetrahydro-1,4-epoxynaphthalenes as conformationally defined analogues of alpha-adrenergic agents.

The exo- and endo-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-1,4-epoxynaphthalenes++ + (3b and 4b, respectively) were prepared and evaluated as conformationally defined analogues of the alpha 1-agonist methoxamine. Only compound 3b exhibited significant alpha 1-agonist activity in the field stimulated rat vas deferens assay. Since 3b closely approximates the antiperiplanar form of (1R,2S)-(-)-erythro-methoxamine, the results suggest that methoxamine interacts with the alpha 1-adrenoceptor in the trans extended form. The exo-guanidino derivative 5 was found to be a partial alpha 1-agonist. Among the exo- and endo-2-amino-1,2,3,4-tetrahydro-1,4-epoxynaphthalenes (3a and 4a, respectively) prepared as rigid analogues of norephedrine, compound 3a possessed agonist activity at both alpha 1- and alpha 2-adrenoceptors, whereas 4a was inactive at either receptor.

Molecular structure of two conformationally restrained fentanyl analogues: cis- and trans-isomers of N-(3-methyl-1-[2-(1,2,3,4-tetrahydro)naphthyl] -4-piperidinyl)-N-phenylpropanamide.

The X-ray crystallographic structures of two analogues of the potent analgetic fentanyl in which the N-phenethyl substituent is restrained through incorporation into a tetrahydronaphthyl ring system are reported. The tetrahydronaphthyl moiety exists in an equatorial conformation with respect to the piperidine ring which exists in the chair conformation. The propanilido group is also equatorial and antiperiplanar. The orientation of the N-phenyl group with respect to the N-acyl moiety is essentially invariant with an approximately 90 degrees dihedral angle. The implications of these conformations in the interaction of fentanyl-type analgetics with opiate receptors are discussed. The following data were obtained: cis-[C25H33N2O+]Cl- . 1/2 C2O4H2, triclinic, P-1; a = 7.005(7), b = 13.189(2), c = 14.312(4)A, alpha = 111.27(2), beta = 99.15(5), gamma = 93.52(4)0, V = 1205.9A, Z = 2, T = 110K, R = 0.0596, Rw = 0.0760; trans-[C25H33N2O+] C2O4H- . 1/2 C2O4H2 . 2 H2O, triclinic, P-1, a = 8.235(6), b = 10.546(8), c = 17.108(9)A, alpha = 107.72(5), beta = 95.73(5), gamma = 90.63(6)0, V = 1406.8A3, Z = 2, T = 110K, R = 0.0737, Rw = 0.0934.

Structure of a Neurotoxin that Induces Parkinsonism Symptoms; l-Methyl-4-phenyl-l,2,3,6-tetra-hydropyridine Hydrochloride.

The X-ray crystal structure of the neurotoxin MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been elucidated. A comparison of the structural relationship of his agent, which induces Parkinsonism by the selective destruction of nigrostriatal dopamine neurons, to the crystal structure of dopamine is presented.

Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse liver preparations.

Using a mouse liver microsomal preparation, it was found that the heterocyclic ring system of MPTP underwent an initial alpha-oxidation to give chemically reactive metabolites that may be associated with the induction of Parkinsonism by MPTP. Subsequent oxidative metabolic transformations of these intermediates were found to give a lactam metabolite and a pyridone metabolite that potentially may interact with the neurotransmitter system.

Conformationally restrained fentanyl analogues. 2. Synthesis and analgetic evaluation of perhydro-1,6-naphthyridin-2-ones.

Conformational flexibility of the N-acyl portion of fentanyl-type analgetics was restricted through the synthesis of novel perhydro-1,6-naphthyridin-2-one derivatives. Neither the cis-fused derivative (5a), the trans-fused derivative(5b), nor the enamide 8a possessed analgetic activity in the mouse tail-flick assay, reaffirming the sensitivity of this portion of 4-anilidopiperidine analgetics to conformational restraint.

Pharmacologic investigation of compounds related to 3,4-methylenedioxyamphetamine (MDA).

The 3-aminobutane homolog (HMDA) of 3,4-methylenedioxyamphetamine (MDA) was synthesized and compared to MDA for acute pharmacologic/toxicologic properties in mice. The lethality of intraperitoneal doses of HMDA equalled or exceeded that of MDA, depending on whether mice were grouped or isolated after dosing. All deaths with HMDA occurred by 6 hours, while many were delayed to 6-24 hours for MDA, particularly in the aggregated condition. Rather similar response patterns were seen for the N-methylated derivatives of MDA and HMDA. Catecholaminergic receptor blockers, haloperidol, propranolol and phenoxybenzamine, which previously were found protective against MDA lethality, were ineffective against HMDA. However, phenoxybenzamine supplemented a protective action of phenobarbital toward HMDA lethality. The dose-related pattern of locomotor activity effects of HMDA differed from the one seen for MDA, which has been suggested to characterize hallucinogenic agents. Thus, HMDA differs qualitatively in actions from MDA and tends to be more toxic acutely for mice.

Rigid analogues of dopamine: synthesis and interaction of 6-exo- and 6-endo-(3',4'-dihydroxyphenyl)-2-azabicyclo[2.2.2]octanes with dopamine uptake sites and receptors.

Two isomeric 6-endo- and 6-exo-(3',4'-dihydroxyphenyl) derivatives (1 and 2) of 2-azabicyclo[2.2.2]octane were synthesized as semirigid analogues of dopamine (DA) to help evaluate the preferred conformation of dopamine at the uptake site of the presynaptic nerve terminal and at the DA receptor. Against the uptake of 0.1 microM [3H]DA by a synaptosomal preparation of corpus striatum from the reserpine-pretreated rat, 2 was found to have a weak inhibitory effect that was three times greater than that of 1 (IC50 = 32 vs. 110 microM). Interactions with DA receptors were assessed with competition for binding of [3H]apomorphine (APO) and on the effect on DA-sensitive adenylate cyclase. Compounds 1 and 2 were both virtually inactive against the binding of 0.5 nM [3H]APO at a screening concentration of 100 microM. The experimental compounds also exhibited only slight adenylate cyclase stimulation in rat striatal homogenates, with 1 appearing to be somewhat more active (at 50 or 400 microM). The weak activities of 1 and 2 and their relatively small differences in activity in these test systems suggest that the DA analogues interact only weakly with the DA transport and receptor sites, possibly as a result of the steric interference caused by the bulky bicyclic ring.

Acute phencyclidine poisoning in the unanesthetized dog: pathophysiologic profile of acute lethality.

Phencyclidine HCl was infused intravenously (1.0 mg/kg/min) to unanesthetized mongrel dogs until death. All animals experienced tonic-clonic convulsions (mean convulsive dose: 4.7 +/- 0.3 mg/kg) which lasted until shortly before death (mean lethal dose: 49.8 +/- 2.5 mg/kg). Significant increases in heart rate, arterial blood pressures, cardiac output, body temperature, and arterial pCO2 were observed in all animals. Significant reductions from pre-drug control values were observed in total peripheral resistance, arterial pH, arterial pO2, and respiratory minute volume. Blood lactate, oxygen uptake, and plasma glucose levels rose to values significantly higher than pre-drug control values then declined during the latter phase of the experiment, glucose levels decreased to final values lower than control. Animals appeared to die of primary respiratory failure, which was exacerbated by hyperthermia, and which resulted in final cardiovascular collapse.

Discriminative stimulus properties of cocaine, norcocaine, and N-allylnorcocaine.

A discriminative stimulus paradigm was employed to train eight male and female Wistar rats to discriminate 5.0 mg/kg cocaine HCl from 2.0 ml/kg saline. Subjects responded in a two bar operant chamber on an FR 30 schedule for food reinforcement. All sessions followed a 10 minute pretreatment with either saline, the training dose of cocaine, four probe doses of cocaine HCl (1.0, 2.5, 7.5, 10 mg/kg), four probe doses of norcocaine (1.0, 2.5, 5.0, 7.5 mg/kg) or four probe doses of N-allylnorcocaine (5.0, 7.5, 10, 20 mg/kg). All probe doses were treated using an extinction procedure. The three highest doses of cocaine generalized to cocaine while the 1.0 mg/kg dose of cocaine generalized to saline. The two highest doses of norcocaine generalized to cocaine while the 2.5 mg/kg dose of norcocaine resulted in 57% responding on the cocaine lever with the 1.0 mg/kg dose generalizing to saline. Only the highest dose of N-allylnorcocaine was found to generalize to cocaine with the intermediate doses resulting in an intermediate level of responding occurring on the cocaine lever. The 5.0 mg/kg dose of N-allylnorcocaine generalized to saline.

Evaluation of 2-azabicyclo[2.2..2]octane analogs of 4-anilidopiperidine analgesics.

Eight analogs of the fentanyl-type analgesics, in which the piperidine ring is restricted into a boat conformation, were evaluated for analgesic activity. All analogs were less active than fentanyl, but interesting conformational and structural relationships were observed. Results of the study are discussed.

Comparative behavioral profile of cocaine and norcocaine in rats and monkeys.

The effects of cocaine and norcocaine were compared using locomotor activity, fixed-ratio 100 (FR 100) and fixed-interval 4 min (FI 4 min) food reinforcement and free feeding paradigms in rat and intravenous self-administration tests in rhesus monkeys. Cocaine was shown to significantly increase locomotor activity at doses of 20 and 40 mg/kg, while norcocaine had no effect at these doses and produced convulsions and death at 60 and 80 mg/kg. Both compounds significantly reduced food consumption at one or more of the doses tested. Cocaine and norcocaine at doses of 20 and 40 mg/kg, produced decreases in FR responding. Cocaine at doses of 10, 20, and 40 mg/kg, produced increases in FI responding; norcocaine had no effect following 10 mg/kg and decreased responding at 20 and 40 mg/kg. Cocaine (0.2 mg/kg/inj) and norcocaine (0.5, 0.2, 0.8 mg/kg/inj) maintained intravenous self-administration in all three monkeys tested. The data indicate that norcocaine is a pharmacologically active metabolite of cocaine which could account for some of the activity heretofore attributed to cocaine. However, the lack of any stimulatory effect of norcocaine or locomotor activity and the lack of increased responding produced by norcocaine on fixed-interval behavior suggest that norcocaine differs qualitatively from cocaine.