Simultaneous computer modelling of control and guanfacine-masked [3H]-MK 912 saturation curves as well as guanfacine competition curves revealed that both alpha 2A- and alpha 2C-adrenoceptor subtypes were present in the guinea pig cerebral cortex. The Kd value of [3H]-MK 912 determined for the alpha 2A-subtype was 403 pM and for the alpha 2C-subtype 79.8 pM; the receptor sites showing capacities 172 and 19.5 fmol/mg protein, respectively. The Kds of guanfacine were 20 and 880 nM for the alpha 2A- and alpha 2C-adrenoceptor, respectively. In the guinea pig kidney [3H]-MK 912 bound to a single saturable site with Kd 8.34 nM and capacity 285 fmol/mg protein, the site showing pharmacological properties like an alpha 2B-adrenoceptor. Binding constants of 22 compounds for the three guinea pig alpha 2-adrenoceptor subtypes were determined by computer modelling competition curves using for the cerebral cortex a "3-curve assay", for the kidney an "1-curve assay", and using [3H]-MK 912 as labelled ligand. Of the tested drugs guanfacine and BRL 44408 were found to be clearly alpha 2A-selective, Spiroxatrine, yohimbine, rauwolscine and WB 4101, as well as [3H]-MK 912 itself, were found to be alpha 2C-selective. The most selective compounds for alpha 2B-adrenoceptors, when compared to alpha 2A-adrenoceptors, were ARC 239 and prazosin. In the guinea pig kidney [3H]-p-aminoclonidine bound to alpha as well as to non-adrenergic imidazoline sites. The alpha 2-adrenoceptors could be completely blocked using 10 microM (-)-adrenaline without the non-adrenergic sites being affected. During these conditions the analysis of combined saturation and competition studies using labelled and unlabelled p-aminoclonidine with computer modelling revealed that the ligand labelled two different sites with Kds of 310 and 47,000 nM, respectively. Competition curves of 16 compounds for the non-adrenergic [3H]-p-aminoclonidine sites were shallow and resolved into two-site fits. For the high affinity [3H]-p-aminoclonidine site the highest affinities were shown by 1-medetomidine, UK-14,304, guanabenz and detomidine; the Kds of these drugs ranging 26-72 nM. All drugs tested showed low but varying affinities for the low affinity [3H]-p-aminoclonidine site. These data indicated that the [3H]-p-aminoclonidine binding sites of the guinea pig kidney are grossly different from the [3H]-idazoxan binding I2-receptors previously demonstrated also to be present in the guinea pig kidney.