Jan R. Flynn

Dopaminergic effects of non-hydroxylated rigid analogs of apomorphine☆

A series of rigid analogs of apomorphine lacking aromatic hydroxyl substitutents were evaluated for dopaminergic properties. Three compounds, N-methyl-N-propyl-2-aminotetralin (Me-Pr-2-AT), N-N-dipropyl-2-aminotetralin (Di-pr-2-AT) and N,N-dipropyl-2-aminoindane (Di-Pr-2-AI) induced emesis in dogs, contralateral circling in unilaterally lesioned rats, and inhibited prolactin secretion. The induced circling responses, however, were attenuated by prior treatment with alpha-methyl-p-tyrosine methyl ester (AMPTME) and the compounds were weak inhibitors of 3-H-dopamine binding in calf caudate homogenates. The possibility that these agents may be metabolically activated in vivo is discussed.

Structure activity relationships of presynaptic dopamine receptor agonists

Structure activity relationship (SAR) studies have identified many structural entities that interact with dopamine receptors. The aminotetralin structure may be regarded as an active moiety of apomorphine. An unanswered question concerns the SAR of the 4,7-dimethoxy indane derivatives. These agents do not appear to match well with models of dopamine receptors. At least there can be little doubt that SAR research has been a powerful stimulus during the past decade for understanding the function, distribution, and spatial aspects of dopamine receptors.

Rapid and simple analysis of DOPA and 5-HTP using high performance liquid chromatography with electrochemical detection

A rapid and simple assay using high performance liquid chromatography with electrochemical detection (HPLC-EC) has been developed for the concurrent measurement of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) extracted from brain tissue. With a one-step process using strong cationic exchange resin this method circumvented conventional solvent extraction and other preparative separations. Extraction efficiencies from tissue were 95.7 +/- 3.5% (n = 12) for DOPA and 96.0 +/- 7.0% (N = 6) for 5-HTP (numbers indicate the mean R/- S.E.M.). The limit of detection following injection of 30 microliter of standard solution was 500 pg for DOPA and 50 pg for 5-HTP. Additionally, the effects of apomorphine and parachlorophenylalanine on DOPA and 5-HTP accumulation were measured following inhibition of DA neuronal firing and aromatic L-amino acid decarboxylase. This method has been proven to be sensitive and selective enough to estimate changes of DA and 5-HT synthesis in discrete brain regions such as caudate nucleus and olfactory tubercle of rat brain.

Antagonist properties of phentolamine at both presynaptic α2-adrenoceptors and presynaptic dopamine receptors using field stimulated right cat atria☆

Phentolamine, which is considered a specific alpha-adrenoceptor antagonist, was tested for antagonist properties at presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors present on sympathetic nerve terminals in isolated right cat atria. Field stimulation induced a transient tachycardia which was inhibited by stimulation of presynaptic dopamine receptors using apomorphine or by stimulation of presynaptic alpha 2-adrenoceptors using clonidine. The presynaptic inhibitory effects of apomorphine were competitively antagonized by sulpiride, which is considered a specific dopamine receptor antagonist, and by phentolamine and yohimbine which are considered alpha-adrenoceptor antagonists. The presynaptic inhibitory effects of clonidine were competitively antagonized by phentolamine and yohimbine but not by sulpiride. pA2 values for phentolamine against apomorphine and phentolamine against clonidine suggest that phentolamine may be an antagonist at both presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors.

Anticholinesterase activity and structure activity relationships of a new series of hemicholinium-3 analogs

Piperidine derivatives of hemicholinium-3 were synthesized and included the following spacing groups between the bis-cationic heads: trans,trans-bicyclohexyl, phenanthrene, naphthalene and biphenyl. Anticholinesterase activity was determined using rat striatal synaptosomal cholinesterase, bovine erythrocyte acetylcholinesterase and horse serum butyrylcholinesterase. Hemicholinium-3 has little anticholinesterase activity but when the choline moiety of hemicholinium-3 is replaced with selected heterocyclic amine ring systems active inhibitors can be obtained. Results in this communication identify several quaternary amines which are equipotent with physostigmine for inhibition of cholinesterase. Several tertiary amines were also found to be active. Optimal anticholinesterase activity of these piperidine derivatives appear to be related to the necessity of 14 A interatomic distance between the cationic heads as well as C = O substitution in the phenylethyl spacing moiety. Reduction of C = O to secondary alcohol or CH2 results in decreased activity. The anticholinesterase activity is not only related to internitrogen distance and C = O substitution but also structural planarity and positional isomerism of the quaternary cationic head.

Inhibitory Receptors on the Adrenergic Nerve Terminal

ABSTRACT The characterization of the type of inhibitory receptors on the adrenergic nerve terminal remains to be determined. The order of activity of various compounds interacting with dopaminergic receptors of the renal vascular bed do not correlate with activity at other dopaminergic sites. A series of cis-trans isomers of octahydrobenzo[f]quinolines has been synthesized and their biological actions reported. These agents are highly potent dopaminergic agents on various preparations. With N-alkyl substitution, only the trans isomers were active as inhibitors of the adrenergic nerve terminal. Both the cis and trans isomers of the secondary amine derivatives were active, but apparently inhibited adrenergic nerve terminals by different mechanisms. The cis isomer appears to interact with alpha adrenergic receptors and the trans isomer with dopaminergic receptors. The trans N- n -propyl derivative is perhaps the most potent agent yet reported to block the adrenergic nerve terminal in the dopaminergic series. The top of the dose response curve is 0.3 μg/kg. The trans tertiary amine isomers were found to be potent emetics in dogs and also potent and of long duration in rats with unilateral denervation of the caudate nucleus.

Dopaminergic activity of cis-trans isomers of benzhydro[f]quinoline analogs

A comparison of the biological activity of isomers with varying alkyl substitutions on the heterocyclic nitrogen of benzhydro[f]quinoline derivatives was made. The secondary amines did not inhibit adrenergic transmission. The trans-isomer of the secondary amine was 0.5 as active as norepinephrine when evaluated for positive chronotropic action in anesthetized cats. The trans-isomers of the N-alkyl derivatives produce inhibition of responses produced by stimulation of cardioaccelerator nerves with doses of 1--5 mumol/kg. Likewise potent emetic activity (dog) and rotational behavior (rat) was observed with the N-alkyl derivatives when administered subcutaneously. The cis-isomers were much less active. The neuronal inhibitions in cats were antagonized by haloperidol 100 micrograms/kg, except the cis-isomer of the N-ethyl derivate which required phentolamine, 2 mg/kg. In general, the transisomers were more potent in contracting the isolated rabbit aorta. This response appeared to be mediated through an alpha-adrenergic mechanism since phentolamine blocked these responses. The trans-isomer TL-305 was effective in relaxing methacholine contracted guinea-pig trachea through a beta-adrenergic mechanism since propranolol blocked this response.

Structure–Activity Relationship Studies of Hemicholinium (HC-3) Congeners

In a continuing investigation of structural requirements for hemicholinium-like activity (inhibition of neuromuscular transmission due to inhibition of uptake of choline into nerve terminals), some additional molecular modifications of hemicholinium (“HC-3”; structure 1) were made. The target compounds were prepared by standard one- or two-step sequences. Noncyclic acetal moieties in general permitted retention of pharmacological activity, as did concomitant replacement of the central bi-phenyl “spacer” by other bulky cyclic groupings and replacement of the oxazinium rings by piperidine or 4-methylpiperidine. However, these modifications generally produced compounds of a lower potency. Replacement of the biphenyl moiety of HC-3 with polyalkylene chains permitted retention of a considerable degree of activity. In these target compounds, the two quaternary nitrogens can exist the same distance apart (approximately 14 Å) as in the hemicholinium molecule. The ditertiary amino congener of a pharmacologically active bis-quaternary oxazinium compound was almost completely inactive. To date, only one tertiary amine has been found which displays a significant degree of hemicholinium-like activity.

Dopamine receptor agonistic activities of R- and S-enantiomers of 4-hydroxy-2-di-n-propylaminoindan in cat hearts.

In‐vitro and in‐vivo studies were used to evaluate the presynaptic dopamine receptor stimulating activities of R‐and S‐enantiomers of 4‐hydroxy‐2‐di‐n‐propylaminoindan in cat hearts. Bioassay results show that the R‐enantiomer is 100 times more potent than the S‐enantiomer in both in‐vitro and in‐vivo preparations.