Louis Brammer Hansen

The γ-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats

The effect of systemic administration of the gamma-aminobutyric acid (GABA) uptake inhibitor, R(-)N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloride (tiagabine) (previously NO-328), on extracellular GABA levels in the globus pallidus, ventral pallidum and substantia nigra of awake Sprague-Dawley rats was investigated using in vivo microdialysis. Tiagabine was administered in doses of 11.5 or 21.0 mg/kg i.p. (ED50 and ED85 doses, respectively, for inhibiting pentylenetetrazole-induced tonic seizures). Tiagabine increased the extracellular concentrations of GABA in globus pallidus with peak values 310% of basal level (after 21 mg/kg) and 240% of basal level (after 11.5 mg/kg). A significant increase in extracellular GABA levels was also found in the ventral pallidum (280% increase after 11.5 mg/kg and 350% increase after 21 mg/kg) and in the substantia nigra where the ED85 dose of tiagabine (21 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.

NNC-112, NNC-687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists

The neurochemical properties of three novel benzazepine derivatives NNC-112, NNC-687 and NNC-756 were assessed. These compounds inhibited dopamine D1 receptor binding in vitro with low nanomolar to picomolar dissociation constants whereas those for the D2 receptor were in the micromolar range. Contrary to classical neuroleptics, but similar to the atypical neuroleptics, clozapine and fluperlapine, NNC-112, NNC-687 and NNC-756 were relatively more potent in inhibiting dopamine-stimulated adenylyl cyclase than [3H]SCH 23390 binding. Both NNC-112 and NNC-756 had high affinity for the 5-HT2 receptor whereas NNC-687 had low affinity for this receptor. The affinity for other receptors or neurotransmitter transporters was very low. In vivo, the dopamine D1 receptor selective profile of NNC-112, NNC-687 and NNC-756 was evident from the potent inhibition of D1 receptor binding whereas no effect on D2 receptor binding was apparent. In addition, the compounds blocked D1 receptor-mediated rotation in unilaterally 6-hydroxydopamine-lesioned rats, but had no effect on D2-induced rotation. Thus, NNC-112, NNC-687 and NNC-756 are potent and selective dopamine D1 receptor antagonists that may be useful in the treatment of schizophrenia.

Alkoxyfurocoumarin derivatives as potential mesolimbic selective antipsychotics

Summary A series of potential antipsychotic compounds have been synthesized by combining a furocoumarin heterocycle through a linker of different sizes with an arylpiperazine or piperidine moiety. Several of the compounds show very high affinity for the dopamine-D 1 and -D 2 , α 1 -adrenergic and serotonin 5-HT 2 receptors in vitro and selected compounds, eg, 3k, 3n and 3p , were active in in vivo models predictive of antipsychotic activity. In mice the compounds potently antagonized methylphenidate-induced motility while methylphenidate-induced gnawing was unaffected. In rats the compounds inhibited condition avoidance responding without causing catalepsy.

[125I]‐ and [14C]‐labelling of the long‐acting insulin derivative NN304

LysϵB29 Tetradecanoyl des(B30) human insulin, Novo Nordisk code no NN304, is a long-acting human insulin derivative that differs from human insulin by being more than 98% albumin bound in plasma. The syntheses of [125I]TyrA14 Nϵ-LysϵB29 Tetradecanoyl des (B30) human insulin ([125I]NN304) and LysϵB29 [I-14C]-Tetradecanoyl des (B30) human insulin ([14C]NN304) used for absorption, distribution, metabolism and excretion (ADME) studies are described. NN304 was radio-iodinated using the lactoperoxidase/hydrogen peroxide method, and the product was isolated using RP-HPLC. Radio-peptide mapping confirmed the [125I] labelling position at Tyrosine 14 in the A-chain. The radio-chemical yield was 30% with a radiochemical purity of >98%. [14C]NN304 was synthesised in two steps starting from 1-[14C] myristic acid and subsequently purified by HPLC. The overall radiochemical yield was 15% with a radiochemical purity >98%. Copyright