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N S Kula

Publications and source records attributed to N S Kula.

68 records · Page 4Linked to original sources
PubMed1982

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.

Adenylyl Cyclases↗
PubMed1982

Aporphines. 39. Synthesis, dopamine receptor binding, and pharmacological activity of (R)-(-)- and (S)-(+)-2-hydroxyapomorphine.

The enantiomers (6aR and 6aS) of 2,10,11-trihydroxyaporphine (THA) were synthesized from thebaine and bulbocapnine and evaluated pharmacologically in vitro in comparison with (-)-apomorphine [(-)-APO] and dopamine by competition with tritiated apomorphine, ADTN, and spiroperidol for binding to a membrane fraction of calf caudate nucleus, as well as for ability to stimulate adenylate cyclase. In all four tests, the rank order of potency was (-)-APO greater than (-)-THA much greater than (+)-THA. Thus, these results extend the impression that the 6aR configuration for hydroxyaporphines is preferred for interactions with putative dopamine receptors and that 2-hydroxylation reduces potency in comparison with 10,11-dihydroxyaporphines.

Adenylyl Cyclases↗
PubMed1981

Aporphines, 36. Dopamine receptor interactions of trihydroxyaporphines. Synthesis, radioreceptor binding, and striatal adenylate cyclase stimulation of 2,10,11-trihydroxyaporphines in comparison with other hydroxylated aporphines.

The presence of the A ring of aporphines and the addition of substituents to it and to other portions of the aporphine ring systems can extend explorations of the dimensions and other characteristics of the dopamine receptors. Accordingly, the synthesis and some physical and pharmacological properties of a series of (-)-2,10,11-trihydroxyaporphines (3a-g) are described. Structure-activity relationships among mono-, di-, and trihydroxyaporphines were evaluated against the high-affinity (nanomolar) binding of [3H]apomorphine (APO) and [3H]spiroperidol (SPR) with a subcellular fraction (P4) of caudate nucleus from bovine brain. In addition, DA-sensitive adenylate cyclase activity was evaluated in homogenates of rat brain striatal tissue. The rank order of displacement of [3H]APO by potent aporphines (IC50 less than or equal to 30 nM) correlated approximately with their ability to stimulate cyclic AMP synthesis. Potency orders against two ligands were dissimilar; for example, increasing the size of N6-alkyl substituents increased potency vs. [3H]SPR but not vs. [3H]APO binding. Moreover, [3H]SPR binding correlated poorly with cyclase activity or [3H]APO binding, suggesting a closer relationship of [3H]APO binding to dopamine-sensitive adenylate cyclase activity.

Adenylyl Cyclases↗
PubMed1980

Chloroethylnorapomorphine, a proposed long-acting dopamine antagonist: interactions with dopamine receptors of mammalian forebrain in vitro.

N-Chloroethylnorapomorphine (NCA) interacts with homogenates of rat corpus striatum to block subsequent stimulation of cyclic AMP synthesis by 50 micro M dopamine (DA) (IC50 30 micro M). The 10-O-methylated (11-monophenolic) analog of NCA is weaker; an O,O'-diester of NCA is inactive. The NCA-induced inhibition is counteracted by coincubation with DA or apomorphine, but not norepinephrine. Blockade by NCA is non-competitive vs. DA and not readily reversed by washing. NCA also competes for binding of 3H-apomorphine to subsynaptosomal calf caudate membranes (IC50 285 nM) with greater potency than the monophenolic or diester analogs. NCA may represent a unique long-acting antagonist of DA receptors.

Adenylyl Cyclases↗
PubMed1980

Oral bioavailability of apomorphine in the rat with a portacaval venous anastomosis.

Orally administered apomorphine failed to produce stereotyped behavior in sham-operated rats, but did so following portacaval venous anastomosis. Brain and serum levels of apomorphine were highly correlated and corresponded with ratings of stereotypy. Tissue levels were undetectable after oral administration of apomorphine in intact rats but in shunted rats, were similar to those found after s.c. injection. These results suggest that a strong first-pass hepatic metabolism may account for the low oral bioavailability of catechol-aporphines.

Administration, Oral↗
PubMed1979

Effects of alternative transmitter amines on cyclic AMP formation in rat brain tissue.

Aromatic amines and related compounds, some of which are taken up and released from nerve terminals, might act at brain receptors ordinarily stimulated by traditional amine neurotransmitters. Several of these compounds were evaluated for their ability to stimulate or impede synthesis of cyclic AMP in rat striatal homogenates and cortical slices. In contrast to catecholamines, most had no effect, consistent with their possible role as false transmitters.

Amines↗
PubMed1979

Plasma levels of apomorphine following intravenous, intraperitoneal and oral administration to mice and rats.

Clinical use of the potent dopaminergic partial-agonist apomorphine (APO) in a wide variety of neuropsychiatric disorders is hampered by a lack of data concerning tissue/plasma levels following various routes of administration. In the present experiments, plasma levels were assessed at various times up to 4 hours after APO administration IV, IP, and PO to mice and rats. Plasma levels of total radioactivity after PO administration of [3H]-APO were 50 to 65% of those seen after IV administration, but brain levels were almost undetectable after PO administration. Organic solvent-extractable concentrations of tritium-labelled material after IV and IP administration of [3H]-APO to mice were significantly lower than the levels of total radioactivity, while after PO administration, these concentrations were minimal. Similar results were observed in rats following IV and PO administration of [3H]-APO.

Administration, Oral↗