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Biomedical subjects

R A Lahti

Publications and source records attributed to R A Lahti.

17 recordsLinked to original sources
PubMed1992

Novel indolodioxanes with antihypertensive effects: potent ligands for the 5-HT1A receptor.

The synthesis and biological evaluation of a new family of tricyclic indolodioxanes is described. These compounds all contain the 2,3-dihydro-7H-1,4-dioxino[2,3-e]indole nucleus and bear substituents at the 2 and/or 8 positions. Thirteen members of this class were prepared and shown to be potent ligands for the 5-HT1A receptor, with several compounds displaying subnanomolar inhibition constants. These compounds also bind to the dopamine D-2 receptor, but generally with higher inhibition constants than those for 5-HT1A. Certain members of this novel structural class show in vivo activity in the mouse hypothermia assay. One of these compounds, U-86192A, has been shown to have antihypertensive effects in the cat, completely eliminating sympathetic nerve discharge at 1 mg/kg iv and lowering mean arterial pressure to 50% pretreatment levels. These effects can be reversed by the administration of spiperone, indicating that U-86192A is acting via a central serotonergic mechanism.

Animals↗
PubMed1992

Pharmacologic properties of (-)-3PPP (preclamol) in man.

The dopamine (DA) autoreceptor agonist (-)-3PPP (preclamol) was tested in male schizophrenic volunteers for safety. The drug was administered intramuscularly in a single rising dose design, crossed with a similar "rising dose" placebo period; all evaluations and raters were blind to drug or placebo administration. Pharmacokinetic, endocrine, safety, and mental status outcome measures were completed before and after each single dose of drug or placebo. Pharmacokinetic analysis showed blood levels between 200-500 pmoles/ml after the intramuscular drug doses of 30-40 mg. Drug half life is 2-2.5 hrs. Growth hormone (GH) levels were elevated in a linear fashion to the 30 mg dose; whereafter, the drug failed to affect GH at all. All safety evaluations were negative, including any untoward effects on the major organ systems. After single dose drug administration, evidence of antipsychotic action occurred in two of the four subjects. This study suggests that (-)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy.

Administration, Oral↗
PubMed1992

Antagonism of kainic acid lesions in the mouse hippocampus by U-54494A and U-50488H.

A morphometric study of kainic acid- (KA) induced lesions was designed for the study of the interaction of the diamines U-5449A and U-50488H with excitatory amino acids, and the dose-response relationship thereof. IC50S determined for binding at the kappa receptor and other opioid receptors demonstrated the lack of kappa activity of U-54494A, a structurally related analog of U-50488H. Both opiate kappa receptor related anticonvulsant diamines were tested for their ability to protect the mouse hippocampus from the cytopathological changes induced by KA in neurons and glia. The damage observed with i.c.v. KA in mouse was restricted to neurons of the CA3 pyramidal region and glia of the hippocampus. It involved massive cell loss and shrunken neurons with dark cytoplasm and nuclei. Groups treated with combinations of KA and U-54494A or U-50488H showed scarce damage, but patches of necrotic changes were still observed. Control animals treated with saline (i.c.v.) and U-54494A (s.c.) or U-50488H (s.c.) did not suffer any noticeable alterations of the polymorphic layers of the hippocampal formation. Image analysis of the CA3 area of the hippocampus was used to quantitate the vacuolization induced by KA lesions in the control and treated groups. By this method, both U-54494A and U-50488H were shown to protect this area in a dose-related fashion as evidenced by reduced vacuolization. The anticonvulsant properties of these compounds may result in the antagonism of the excitotoxic lesions. More specifically, the ability of these diamines to block depolarization-induced influxes of Ca++ may protect the CA3 cells from the cytotoxic effects of persistent depolarization.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Intrinsic activity determinations at the dopamine D2 guanine nucleotide-binding protein-coupled receptor: utilization of receptor state binding affinities.

Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity agonist (HiAg) and a low affinity agonist (LowAg) state. The formation of the HiAg state is promoted by agonists, and the formation of this state of the receptor appears to be a critical factor in the generation of the effector-activating complex G alpha.GTP.Mg2+ and in the production of a stimulus. The magnitude of the difference in the affinity a compound has for the HiAg versus the LowAg state of the receptor has been related to the intrinsic activity of the compound. In this paper the HiAg and LowAg affinities (Ki) of full and partial dopamine agonists of varying levels of intrinsic activity were determined using membranes from Chinese hamster ovary cells stably transfected with the D2i receptor. The HiAg state was defined using the recently described dopamine agonist ligand [3H]U-86170, and the LowAg state was defined using [3H] raclopride plus 600 microM GTP. The LowAg/HiAg ratios for apomorphine (43), HW-165 (12.5), (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(-)-3-PPP] (4.5), terguride (1.6), SDZ-208-911 (1.2), and SDZ-208-912 (0.3) were found to correlate well with their electrophysiologically derived intrinsic activities (r = 0.92). Using this relationship, the intrinsic activity for compounds such as (+)-3-PPP (112%), quinpirole (104%), U-68553B (102%), and U-86170 (95%) was predicted to be high (greater than 90%); (-)-apomorphine (73%) was of high/moderate intrinsic activity, HW-165 (52%), (+)-apomorphine (51%), and (-)-3-PPP (34%) were in the intermediate range, and terguride (16.5%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were at the lower end of the intrinsic activity spectrum. The receptor state binding-determined intrinsic activity values for quinpirole (100%), U-86170F (94.8%), HW-165 (52.1%), (-)-3-PPP (34.3%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were found to correlate well (r = 0.908) with their maximum response (intrinsic activity), as determined using ATP-mediated increases in arachidonic acid release from CHO-D2i cells. In addition, the maximal effect of several of these compounds on rat striatal homovanillic acid (HVA) levels was determined. The drug-induced changes in tissue HVA levels were found to be consistent with the affinity-derived intrinsic activities of the drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminoquinolines↗
PubMed1991

Dopamine D2 receptor binding properties of [3H]U-86170, a dopamine receptor agonist.

U-86170F, an imidazoguinolinone, is a potent dopamine D2 agonist, binding with high affinity to the dopamine D2 receptor. A Kd of 0.99 nM was determined in membranes from Chinese hamster ovarian (CHO) cells transfected with the D2 receptor and a Kd of 1.72 nM was obtained in rat striatal homogenates. GTP sensitivity was demonstrated when its addition (300 microM) reduced [3H]U-86170 binding by 60%. This agonist ligand is especially effective in identifying agonists and partial agonists, as well as antagonists, and affords a more precise evaluation of their affinity for the dopamine D2 receptor, without the use of multiple site analysis, than does an antagonist [3H]-ligand.

Aminoquinolines↗
PubMed1991

Pre- and postsynaptic dopaminergic activities of U-86170F.

The biochemical, endocrine, receptor binding, and behavioral effects of the putative dopamine autoreceptor agonist, U-86170F, were evaluated in various in vivo and in vitro models. U-86170F and apomorphine were shown to cause a significant reversal of the effects of gamma-butyrolactone (GBL) on dopamine accumulation in mouse striata. In contrast to apomorphine, U-86170F had a ceiling effect on the extent of the reversal of GBL effects (55%), whereas apomorphine had an 82% reversal. The effect on striatal homovanillic acid (HVA) levels was also monitored, and both compounds exerted a similar and significant reduction in striatal HVA. A comparison was made between the effects of intraperitoneal (i.p.) and oral administration of U-86170F in the alpha-methyl-p-tyrosine (alpha-MPT)/prolactin model in rats. When administered by the i.p. route, U-86170F suppressed the effects of alpha-MPT on prolactin level increase, having an ED50 of about 0.03 mg/kg, and when administered by the oral route, its ED50 was approximately 0.1 mg/kg. U-86170F has been shown to be a potent dopamine autoreceptor agonist in the GBL, prolactin, and HVA models, with an effective i.p. dose of approximately 0.03 mg/kg. When evaluated for postsynaptic dopaminergic activity in the reserpinized mouse model, and compared to apomorphine, U-86170F was found to increase locomotor activity, but its maximum effect was only 65% of that attained with apomorphine. Higher doses were needed for postsynaptic effects. In receptor binding studies using cloned D2 receptor preparations, U-86170F was found to exhibit agonist binding properties similar to dopamine as demonstrated by their inhibition of 3H-raclopride binding.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗
PubMed1991

Naphtho and benzo analogues of the kappa opioid agonist trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide.

Further elaboration on the structure-activity relationships in our U-50,488 series has revealed that benzologation of this cyclohexane-1,2-diamine derivative provides compounds which either maintain the interaction with the kappa receptor (e.g. compounds 3a and 5a in the phenylacetamido series) or eliminate the mu receptor mediated analgesia (e.g. compounds 3-6 in the benzamido series). Naphthologation also caused the elimination of mu receptor mediated analgesia (e.g. compounds 17a and 17b).

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1979

Antidepressant and antipsychotic agents.

Numerous studies have been reviewed concerning the relationship of the catecholamines and indoleamines to depression and its treatment with antidepressant drugs. The profusion of data on the subject suggests the amines may be implicated in the disease, however no convincing hypothesis is available which unites the two. A similar situation seems to exist concerning the antipsychotic agents, dopamine and schizophrenia. The evidence appears to be overwhelming relating dopamine in the action of these agents and yet serious inconsistencies have been reported suggesting the need for a revision of the hypothesis regarding the mode of action of antipsychotic agents.

Antidepressive Agents↗
PubMed1978

Novel anxiolytic agents derived from alpha-amino-alpha-phenyl-o-tolyl-4H-triazoles and -imidazoles.

Several new alpha-amino-alpha-phenyl-o-tolytriazoles and -imidazoles have been prepared in one step by means of a novel reductive rearrangement of the corresponding benzodiazepines with hydrazine hydrate. These new triazoles were found to have moderate sedative and muscle relaxing activity in mice (i.e., these compounds depressed the traction and dish reflexes at higher doses than did diazepam) but were very potent antagonists of the clonic convulsions induced in mice by the administration of pentylenetetrazole. Furthermore, they antagonized the lethality induced by thiosemicarbazide. While these new compounds were very active in mice, most were inactive in rats. These results are discussed with reference to the metabolism of compound 13.

Animals↗
PubMed1977

The metabolism of biogenic amines in experimental animals and in human subjects during acute and chronic administration of ethanol.

Ethanol has been shown to induce a shift in catecholamine metabolism peripherally from normally oxidative pathways to reductive pathways. The mechanisms of this effect may result from competitive inhibition of aldehyde dehydrogenase by acetaldehyde. The shift in metabolism cannot be found in brain and alterations in catecholamine function may reflect changes in the turnover of these amines.

Acetaldehyde↗
PubMed1976

Synthesis and pharmacology of novel anxiolytic agents derived from 2-[(dialkylamino)methyl-4H-triazol-4-yl] benzophenones and related heterocyclic benzophenones.

A series of novel [(dialkylamino)methyl-4H-1,2,4-triazol-4-yl]benzophenones and related compounds has been prepared via total synthesis from substituted aminodiphenylmethanes or by hydrolysis and subsequent methylation of triazolobenzodiazepines. These new triazole compounds were found to have potent sedative and muscle relaxing activity in mice (i.e., these compounds depressed the traction and dish reflexes). In addition, the title compounds antagonized the clonic convulsions induced in mice by the administration of pentylenetratrazole (Metrazol, 85 mg/kg), with ED50's varying from 2.0 to 23.0 mg/kg, and the lethality induced by thiosemicarbazide, with ED50's varying from 0.02 to 9.0 mg/kg. In several biological tests, the potency of seven new benzophenone derivatives approached or exceed that of diazepam (35a) or its glycylaminobenzophenone analogue 36.

Animals↗
PubMed1976

Conversion of N-alkylaminobenzophenones to benzodiazepines in vivo.

The results of this study suggest that 5-chloro-2-[3-methyl-5-(dimethylamino)methyltriazol-4-yl]benzophenone can undergo N-dealkylation and ring closure in vivo to form the corresponding benzodiazepine. The in vivo conversion was found to occur in mice, rats, and monkeys. A variety of substituted aminobenzophenone compounds were also able to undergo these conversions. The conversions to benzodiazepines were confirmed by a comparison of retention times on a gas chromatograph as well as through the use of a GC-mass spectrometer. The results obtained did not prove that the N-alkylaminobenzophenones were devoid of activity, but they do suggest that their observed pharmacological activity may be due to the formation of the corresponding benzodiazepines.

Animals↗
PubMed1975

The effect of various doses of minor tranquilizers on plasma corticosteroids in stressed rats.

Minor tranquilizers have been shown to be specific inhibitors of the elevation of plasma corticosteroid levels in rats subjected to mild stress. The inability of several anxiolytic compounds to show activity at high doses prompted an investigation of the effect on corticosteroid levels of these drugs over a wider dosage range. It was found that at high doses, the drugs themselves cause an elevation of corticosteroid levels masking the blocking of the stress-induced elevations. It was discovered that upon sub-chronic administration, the drug-induced elevation diminishes while the ability to inhibit stress-induced elevation persists. Finally, an extensive dose response curve for phenobarbital demonstrated a variety of responses, depending upon the dose; an antistress effect at low dose, a relatively ineffective dose range from 50-100 mg/kg, and a corticosteroid lowering effect at anesthetic doses. The lack of effect of moderately high doses has been explained through their depressant side effects, which in themselves are stressful to the animal.

Adrenal Cortex Hormones↗