Abstract

Alkyl and arylalkyl derivatives of the dopamine (DA) D2 antagonist spiperone were prepared and characterized chemically and pharmacologically. They included the N-methyl, N-phenethyl (NPS), and N-p-aminophenethyl (NAPS) derivatives, as well as the alkylating isothiocyanato (NIPS), bromacetamido, and ethylfumaramido p-substituted N-phenethylspiperones. These compounds showed high lipophilicity (log P up to 6.0 with NIPS), as well as very high in vitro D2 affinity (Ki = 35-280 pM) and D2 versus D1 selectivity (540-9000-fold) in radioreceptor assays with corpus striatum of rat brain. Of the alkylating series, NIPS showed the highest D2 affinity (57 pM) and D2 versus D1 selectivity (2040-fold) and so was selected for further evaluation. NPS, NAPS, and NIPS showed little or no affinity for 34 non-DA binding sites defined by radioligand assays for monoamine, amino acid, and peptide neurotransmitters, ion channels, peptide growth factors, and transmission mediators but did show low alpha 2 and moderate alpha 1 and 5-hydroxytryptamine (5-HT2) affinity with rat forebrain tissue in vitro; NIPS showed a marked gain in D2 versus 5-HT2 selectivity, compared with spiperone (1520- versus 26-fold). Systemic injections of NIPS induced marked decreases in rat striatal D2 binding sites 24 hr later, with little effect on D1, 5-HT2, or alpha 1 sites; NIPS and NAPS lowered apparent Bmax values at D2 receptors with little change in ligand affinity, ex vivo as well as in vitro. NPS, NAPS, and NIPS all induced dose-dependent lowering of D2 binding ex vivo (ID50 = 1-9 mumol/kg, intraperitoneally) and blocked the behavioral effects of the DA agonist apomorphine (0.9 mumol/kg) potently (ID50 = 0.3-0.5 mumol/kg) at 24 hr. Recovery from these anti-DA actions required about 1 week after equimolar (15 mumol/kg) and similarly effective doses of NPS and NAPS, as well as NIPS. Thus, highly selective and avidly bound lipophilic D2 affinity ligands with similarly avid in vitro and prolonged in vivo anti-DA activities can be derived from N-phenethylspiperones with or without an alkylating moiety present. Such affinity ligands may represent useful additions to previously used, generally less selective, D2 affinity ligands.