3 Naphazoline, guanabenz, clonidine and amiloride competition studies had Hill slopes which were significantly different from unity (P<0.01) and computer analysis showed that the [3H]-idazoxan binding data could be best fitted to a model which considers binding to two sites (P<0.01). One site has a high affinity for idazoxan, cirazoline, naphazoline, guanabenz and amiloride and a moderate affinity for BRL44408 and clonidine (70% of binding) and the second site (30% of binding) has a high affinity for idazoxan and cirazoline, but a lower affinity for naphazoline, guanabenz, amiloride, BRL44408 and clonidine. 4 Experiments using [3H]-RX821002, in contrast to [3H]-idazoxan, clearly demonstrated the presence of a single type of M2-adrenoceptor in rabbit cortex with a pharmacological profile which is similar to the aX2A-adrenoceptor possessing a high affinity for yohimbine, rauwolscine, BRL44408 and oxymetazoline, but a lower affinity for prazosin. 5 The monoamine oxidase inhibitors, clorgyline, pargyline and deprenyl had at least a ten fold lower affinity at the rabbirt cortex '2 site as compared to their known affinity at monoamine oxidase suggesting that the 12 site is not related to the active site of the enzyme, monoamine oxidase. In addition, the peripheral benzodiazepine ligands, PK-11195 or Ro 5-4864 both had very low affinities at the I2 site in rabbit cortex suggesting that the [3H]-idazoxan binding was not to the peripheral benzodiazepine binding site.
Akuammine [1], an indolomonoterpene alkaloid, which is the major component of the seeds of Picralima nitida, was reduced to dihydroakuammine [4]. This compound has structural analogy with eseroline [7], for which affinity for opiate receptors was reported. The present investigation showed that 1 and 4 also bind (with lower affinity however) to mu and kappa opiate receptors. 1H- and 13C-nmr spectra of 1 and 4 have been fully assigned by 2D nmr experiments.
Brain extraction of a tricyclic antidepressant, imipramine, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins and erythrocytes could inhibit the brain extraction was measured. Equilibrium dialysis showed that imipramine is highly bound to human serum albumin (HSA), alpha 1-acid glycoprotein (AAG), lipoproteins, and erythrocytes. The free dialyzable drug fraction was inversely related to the protein concentration. Despite this degree of binding, no significant reduction in the brain extraction of the drug was observed in the presence of HSA, lipoprotein, or erythrocytes. Only AAG reduced the brain transport of this drug in a ratio related to the protein concentration. However, the rat brain extraction was higher than expected from the in vitro measurement of the dialyzable fraction. These data indicate that the amount of circulating imipramine available for penetration in brain exceeds widely the dialyzable fraction of the drug as measured in vitro.
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